CA2734363C - Substituted pyrrolidine-2-carboxamides - Google Patents
Substituted pyrrolidine-2-carboxamides Download PDFInfo
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- CA2734363C CA2734363C CA2734363A CA2734363A CA2734363C CA 2734363 C CA2734363 C CA 2734363C CA 2734363 A CA2734363 A CA 2734363A CA 2734363 A CA2734363 A CA 2734363A CA 2734363 C CA2734363 C CA 2734363C
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Abstract
There are provided compounds of the formula (I) wherein X, Y, R1, R2, R3, R3, R4, R5, R6 and R7 are as described herein and enantiomers and pharmaceutically acceptable salts and esters thereof. The compounds are useful as anticancer agents.
Description
DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.
NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.
JUMBO APPLICATIONS / PATENTS
THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.
NOTE: For additional volumes please contact the Canadian Patent Office.
p53 is a tumor suppresser protein that plays a central role in protection against development of cancer. It guards cellular integrity and prevents the propagation of permanently damaged clones of cells by the induction of growth arrest or apoptosis. At the molecular level, p53 is a transcription factor that can activate a panel of genes implicated in the regulation of cell cycle and apoptosis. p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can bind p53 and inhibit its ability to transactivate p53-regulated genes. In addition, MDM2 mediates the ubiquitin-dependent degradation of p53. p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein. This feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating cells. MDM2 is also a cofactor for E2F, which plays a central role in cell cycle regulation.
The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. Frequently occurring molecular defects in the p16INK4/p19ARF locus, for instance, have been shown to affect MDM2 protein degradation. Inhibition of MDM2-p53 interaction in tumor cells with wild-type p53 should lead to accumulation of p53, cell cycle arrest and/or apoptosis.
MDM2 antagonists, therefore, can offer a novel approach to cancer therapy as single agents or in combination with a broad spectrum of other antitumor therapies. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of MDM2-p53 interaction (e.g.
antibodies, antisense oligonucleotides, peptides). MDM2 also binds E2F through a conserved binding region as p53 and activates E2F-dependent transcription of cyclin A, suggesting that MDM2 antagonists might have effects in p53 mutant cells.
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.
NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.
JUMBO APPLICATIONS / PATENTS
THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.
NOTE: For additional volumes please contact the Canadian Patent Office.
p53 is a tumor suppresser protein that plays a central role in protection against development of cancer. It guards cellular integrity and prevents the propagation of permanently damaged clones of cells by the induction of growth arrest or apoptosis. At the molecular level, p53 is a transcription factor that can activate a panel of genes implicated in the regulation of cell cycle and apoptosis. p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can bind p53 and inhibit its ability to transactivate p53-regulated genes. In addition, MDM2 mediates the ubiquitin-dependent degradation of p53. p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein. This feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating cells. MDM2 is also a cofactor for E2F, which plays a central role in cell cycle regulation.
The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. Frequently occurring molecular defects in the p16INK4/p19ARF locus, for instance, have been shown to affect MDM2 protein degradation. Inhibition of MDM2-p53 interaction in tumor cells with wild-type p53 should lead to accumulation of p53, cell cycle arrest and/or apoptosis.
MDM2 antagonists, therefore, can offer a novel approach to cancer therapy as single agents or in combination with a broad spectrum of other antitumor therapies. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of MDM2-p53 interaction (e.g.
antibodies, antisense oligonucleotides, peptides). MDM2 also binds E2F through a conserved binding region as p53 and activates E2F-dependent transcription of cyclin A, suggesting that MDM2 antagonists might have effects in p53 mutant cells.
2 The present invention provides compounds of the formula N
R3 \
X
Y = R1 \\
N
I
wherein X is selected from the group consisting of H, F, Cl, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy;
Y is one to four group(s) independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, nitro, lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl, hetereoaryl, hetereocycle, COOR', OCOR', CONR'R", NR'COR", NR"SO2R', SO2NR'R"
and NR'R", wherein R' and R" is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetereoaryl or substituted or unsubstituted hetereocycle; and in the case of R' and R" may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle, one of R1 and R2 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl and the other is hydrogen or lower alkyl;
R3 is H or lower alkyl;
one of R4 and R5 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen;
R6 and R7 are selected from the group consisting of (CH2)-R% (CH2).-NR'R", (CH2).-NR'COR", (CH2)11-NR'SO2R", (CH2)11-COOH, (CH2)11-COOR', (CH2)õ-CONR'R", (CH2)11-OR',
R3 \
X
Y = R1 \\
N
I
wherein X is selected from the group consisting of H, F, Cl, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy;
Y is one to four group(s) independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, nitro, lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl, hetereoaryl, hetereocycle, COOR', OCOR', CONR'R", NR'COR", NR"SO2R', SO2NR'R"
and NR'R", wherein R' and R" is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetereoaryl or substituted or unsubstituted hetereocycle; and in the case of R' and R" may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle, one of R1 and R2 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl and the other is hydrogen or lower alkyl;
R3 is H or lower alkyl;
one of R4 and R5 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen;
R6 and R7 are selected from the group consisting of (CH2)-R% (CH2).-NR'R", (CH2).-NR'COR", (CH2)11-NR'SO2R", (CH2)11-COOH, (CH2)11-COOR', (CH2)õ-CONR'R", (CH2)11-OR',
3 PCT/EP2009/061610 (CH2)õ-SR', (CH2)õ-SOR', (CH2)õ-SO2R', (CH2)õ-COR', (CH2)õ-S03H, (CH2)õ-SONR'R", (CH2)õ-SO2NR'R", (CH2CH20),,,-(CH2),,-R', (CH2CH20)11,-(CH2),,-OH, (CH2CH20).-(CH2),,-OR', (CH2CH20),,,-(CH2)õ-NR'R", (CH2CH20),,,-(CH2),,,-NR'COR", (CH2CH20).-(CH2).-NR'SO2R", (CH2CH20),,,-(CH2),,-COOH, (CH2CH20),,,-(CH2)õ-COOR', (CH2CH20),,,-(CH2)n-CONR'R", (CH2CH20)õ,,-(CH2)õ-SO2R', (CH2CH20),,,-(CH2)õ-COR', (CH2CH20)õ,-(CH2)õ-SONR'R", (CH2CH20),,,-(CH2).-SO2NR'R", (CH2)p-(CH2CH20),,,-(CH2).-R% (CH2)p-(CH2CH20)õ,-(CH2)õ-OH, (CH2)p-(CH2CH20),õ,-(CH2),,-OR', (CH2)p-(CH2CH20)õ,-(CH2)õ-NR'R", (CH2)p-(CH2CH20),,,-(CH2),,-NR'COR", (CH2)p-(CH2CH20)õ,-(CH2),,-NR'502R", (CH2)p-(CH2CH20),,,-(CH2).-COOH, (CH2)p-(CH2CH20).-(CF12).-COOR', (CH2)p-(CH2CH20),,,-(CH2)õ-CONR'R", (CH2)p-(CH2CH20),,,-(CH2),,-S02R', (CH2)p-(CH2CH20),,,-(CH2),,-COR', (CH2)p-(CH2CH20)õ,-(CH2)õ-SONR'R", (CH2)p-(CH2CH20),,,-(CH2)õ-SO2NR'R", -COR', -SOR' and SO2R' wherein R' and R" are the same definitions as above;
m, n and p are independently 0 to -6;
and the pharmaceutically acceptable salts and esters thereof Preferred are compounds of formula I having a stereochemical structure as shown as formula II
I
0N--.R6 R4. E< R3 __ ,.. ________________________________________ (õ% R2 _ \\ R1 Or X N
Y II
wherein X is selected from the group consisting of H, F, Cl, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy;
Y is one to four group(s) independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, nitro, lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl, hetereoaryl, hetereocycle, COOR', OCOR', CONR'R", NR'COR", NR"502R', SO2NR'R"
and NR'R" wherein R' and R" are independently selected from H or substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted lower alkenyl,
m, n and p are independently 0 to -6;
and the pharmaceutically acceptable salts and esters thereof Preferred are compounds of formula I having a stereochemical structure as shown as formula II
I
0N--.R6 R4. E< R3 __ ,.. ________________________________________ (õ% R2 _ \\ R1 Or X N
Y II
wherein X is selected from the group consisting of H, F, Cl, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy;
Y is one to four group(s) independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, nitro, lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl, hetereoaryl, hetereocycle, COOR', OCOR', CONR'R", NR'COR", NR"502R', SO2NR'R"
and NR'R" wherein R' and R" are independently selected from H or substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted lower alkenyl,
4 substituted or unsubstituted lower cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetereoaryl or substituted or unsubstituted hetereocycle, and wherein R' and R" may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle;
R, is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
R2 is hydrogen or lower alkyl;
R3 is H or lower alkyl;
R5 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
R4 is hydrogen;
R6 and R7 are selected from the group consisting of (CH2),,-R', (CH2).-NR'R", (CH2).-NR'COR", (CH2)11-NR'SO2R", (CH2)11-COOH, (CH2)11-COOR', (CH2)-CONR'R", (CH2)11-OR', (CH2)õ-SR', (CH2)11-SOR', (CH2)-SO2R', (CH2)11-COR', (CH2)-S03H, (CH2)-SONR'R", (CH2),,-SO2NR'R", (CH2CH20)õ,-(CH2).-R', (CH2CH20)õ,-(CH2)11-OH, (CH2CH20)õõ-(CH2),,-OR', (CH2CH20),1,-(CH2),,-NR'R", (CH2CH20),,-(CH2),,-NR'COR", (CH2CH20)m-(CH2)n-NR'S02R", (CH2CH20).,-(CH2)õ,-COOH, (CH2CH20),11-(CH2)õ,-COOR', (CH2CH20).,-(CH2)õ,-CONR'R", (CH2CH20)-(CH2)-SO2R', (CH2CH20)m-(CH2)-COR', (CH2CH20)m-(CH2)õ,-SONR'R", (CH2CH20),n-(CH2)õ-SO2NR'R", (CH2)p-(CH2CH20)m-(CH2),,-R', (CH2)p-(CH2CH20)m-(CH2)õ-OH, (CH2)p-(CH2CH20).,-(CH2)õ,-OR', (CH2)p-(CH2CH20).,-(CH2)õ,-NR'R", (CH2)p-(CH2CH20)m-(CH2)õ-NR'COR", (CH2)p-(CH2CH20)m-(CH2)õ,-NR'SO2R", (CH2)p-(CH2CH20)m-(CH2).-COOH, (CH2)p-(CH2CH20)m-(CH2).-COOR', (CH2)p-(CH2CH20)m-(CH2)õ-CONR'R", (CH2)p-(CH2CH20)m-(CH2)õ,-SO2R', (CH2)p-(CH2CH20)õ,-(CH2)õ-COR', (CH2)p-(CH2CH20).,-(CH2)õ,-SONR'R", (CH2)p-(CH2CH20).,-(CH2)õ,-SO2NR'R", -COR', -SOR' and SO2R' wherein R' and R" are the same definitions as above;
m, n, and p are independently 0 to-6; and the pharmaceutically acceptable salts and esters thereof.
Especially preferred are compounds of formula II wherein X is F, Cl or Br;
Y is one to two group(s) independently selected from the group consisting of H, F, Cl, Br, 1, CN, OH, nitro, lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, lower cycloalkenyl and lower alkynyl;
R1 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl,
R, is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
R2 is hydrogen or lower alkyl;
R3 is H or lower alkyl;
R5 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
R4 is hydrogen;
R6 and R7 are selected from the group consisting of (CH2),,-R', (CH2).-NR'R", (CH2).-NR'COR", (CH2)11-NR'SO2R", (CH2)11-COOH, (CH2)11-COOR', (CH2)-CONR'R", (CH2)11-OR', (CH2)õ-SR', (CH2)11-SOR', (CH2)-SO2R', (CH2)11-COR', (CH2)-S03H, (CH2)-SONR'R", (CH2),,-SO2NR'R", (CH2CH20)õ,-(CH2).-R', (CH2CH20)õ,-(CH2)11-OH, (CH2CH20)õõ-(CH2),,-OR', (CH2CH20),1,-(CH2),,-NR'R", (CH2CH20),,-(CH2),,-NR'COR", (CH2CH20)m-(CH2)n-NR'S02R", (CH2CH20).,-(CH2)õ,-COOH, (CH2CH20),11-(CH2)õ,-COOR', (CH2CH20).,-(CH2)õ,-CONR'R", (CH2CH20)-(CH2)-SO2R', (CH2CH20)m-(CH2)-COR', (CH2CH20)m-(CH2)õ,-SONR'R", (CH2CH20),n-(CH2)õ-SO2NR'R", (CH2)p-(CH2CH20)m-(CH2),,-R', (CH2)p-(CH2CH20)m-(CH2)õ-OH, (CH2)p-(CH2CH20).,-(CH2)õ,-OR', (CH2)p-(CH2CH20).,-(CH2)õ,-NR'R", (CH2)p-(CH2CH20)m-(CH2)õ-NR'COR", (CH2)p-(CH2CH20)m-(CH2)õ,-NR'SO2R", (CH2)p-(CH2CH20)m-(CH2).-COOH, (CH2)p-(CH2CH20)m-(CH2).-COOR', (CH2)p-(CH2CH20)m-(CH2)õ-CONR'R", (CH2)p-(CH2CH20)m-(CH2)õ,-SO2R', (CH2)p-(CH2CH20)õ,-(CH2)õ-COR', (CH2)p-(CH2CH20).,-(CH2)õ,-SONR'R", (CH2)p-(CH2CH20).,-(CH2)õ,-SO2NR'R", -COR', -SOR' and SO2R' wherein R' and R" are the same definitions as above;
m, n, and p are independently 0 to-6; and the pharmaceutically acceptable salts and esters thereof.
Especially preferred are compounds of formula II wherein X is F, Cl or Br;
Y is one to two group(s) independently selected from the group consisting of H, F, Cl, Br, 1, CN, OH, nitro, lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, lower cycloalkenyl and lower alkynyl;
R1 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl,
5 substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
R2 is hydrogen;
R3 is H;
R5 is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R4 is hydrogen;
R6 and R7 are selected from the group consisting of (CH2)õ,-R', (CH2)11-NR'R", (CH2).-NR'COR", (CH2),,-NR'SO2R", (CH2),,-COOH, (CH2)11-COOR', (CH2)õ-CONR'R", (CH2)11-OR', (CH2)õ-SR', (CH2)11-SOR', (CH2)õ-SO2R', (CH2)11-COR', (CH2)õ-S03H, (CH2)-SONR'R", (CH2)õ-SO2NR'R", (CH2CH20)m-(CH2)õ-R', (CH2CH20)m-(CH2)õ-OH, (CH2CH20)m-(CH2).-OR', (CH2CH20)õ,-(CH2)11-NR'R", (CH2CH20)m-(CH2)õ-NR'COR", (CH2CH20)õ,-(CH2),,-NR'S02R", (CH2CH20),,-(CH2),,-COOH, (CH2CH20).-(CH2),,-COOR', (CH2CH20),,-(CH2)n-CONR'R", (CH2CH20)õ,-(CH2)õ-SO2R', (CH2CH20)m-(CH2)õ,-COR', (CH2CH20)õ,-(CH2),,-SONR'R", (CH2CH20)õ,-(CH2),,-SO2NR'R", (CH2)p-(CH2CH20),.-(CH2),,-R', (CH2)p-(CH2CH20)m-(CH2).-OH, (CH2)p-(CH2CH20),,-(CH2),,-OR', (CH2)p-(CH2CH20)m-(CF12)n-NR'R", (CH2)p-(CH2CH20)m-(CH2)õ-NR'COR", (CH2)p-(CH2CH20)m-(CH2)õ,-NR'502R", (CH2)p-(CH2CH20)õ,-(CH2)õ-COOH, (CH2)p-(CH2CH20).,-(CH2)-COOR', (CH2)p-(CH2CH20)m-(CH2).-CONR'R", (CH2)p-(CH2CH20),,,-(CH2),,-SO2R', (CH2)p-(CH2CH20)m-(CH2)õ-COR', (CH2)p-(CH2CH20)m-(CH2)õ,-SONR'R", (CH2)p-(CH2CH20),11-(CH2)õ,-SO2NR'R", -COR', -SOR' and SO2R' wherein R' and R" are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetereocycle, or substituted hetereocycle,and wherein R' and R"
may also independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle;
m, n and p are independently 0 to 6; and the pharmaceutically acceptable salts and esters thereof.
R2 is hydrogen;
R3 is H;
R5 is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R4 is hydrogen;
R6 and R7 are selected from the group consisting of (CH2)õ,-R', (CH2)11-NR'R", (CH2).-NR'COR", (CH2),,-NR'SO2R", (CH2),,-COOH, (CH2)11-COOR', (CH2)õ-CONR'R", (CH2)11-OR', (CH2)õ-SR', (CH2)11-SOR', (CH2)õ-SO2R', (CH2)11-COR', (CH2)õ-S03H, (CH2)-SONR'R", (CH2)õ-SO2NR'R", (CH2CH20)m-(CH2)õ-R', (CH2CH20)m-(CH2)õ-OH, (CH2CH20)m-(CH2).-OR', (CH2CH20)õ,-(CH2)11-NR'R", (CH2CH20)m-(CH2)õ-NR'COR", (CH2CH20)õ,-(CH2),,-NR'S02R", (CH2CH20),,-(CH2),,-COOH, (CH2CH20).-(CH2),,-COOR', (CH2CH20),,-(CH2)n-CONR'R", (CH2CH20)õ,-(CH2)õ-SO2R', (CH2CH20)m-(CH2)õ,-COR', (CH2CH20)õ,-(CH2),,-SONR'R", (CH2CH20)õ,-(CH2),,-SO2NR'R", (CH2)p-(CH2CH20),.-(CH2),,-R', (CH2)p-(CH2CH20)m-(CH2).-OH, (CH2)p-(CH2CH20),,-(CH2),,-OR', (CH2)p-(CH2CH20)m-(CF12)n-NR'R", (CH2)p-(CH2CH20)m-(CH2)õ-NR'COR", (CH2)p-(CH2CH20)m-(CH2)õ,-NR'502R", (CH2)p-(CH2CH20)õ,-(CH2)õ-COOH, (CH2)p-(CH2CH20).,-(CH2)-COOR', (CH2)p-(CH2CH20)m-(CH2).-CONR'R", (CH2)p-(CH2CH20),,,-(CH2),,-SO2R', (CH2)p-(CH2CH20)m-(CH2)õ-COR', (CH2)p-(CH2CH20)m-(CH2)õ,-SONR'R", (CH2)p-(CH2CH20),11-(CH2)õ,-SO2NR'R", -COR', -SOR' and SO2R' wherein R' and R" are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetereocycle, or substituted hetereocycle,and wherein R' and R"
may also independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle;
m, n and p are independently 0 to 6; and the pharmaceutically acceptable salts and esters thereof.
6 Further preferred are compounds of formula 11 wherein X is F, Cl or Br;
Y is a mono-substituting group selected from H or F; and R1 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl.
Further preferred R1 is a substituted lower alkyl selected from * R9 R
R
where R8, R9 are both methyl, or linked to form a cyclopropyl, cyclobutyl, cyclopentyl or acyclohexyl group;
R10 is (CH2)m-Rii;
m is 0, 1 or 2;
R11 is selected from hydrogen, hydroxyl, lower alkyl, lower alkoxy, aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle, R2 iS H;
R3 iS H;
R5 is a substituted phenyl selected from:
W W W
or .* V 11101 *
=
11011 ;
W is F, Cl or Br;
V is H or F;
R4 is hydrogen;
one of R6 and R7 is hydrogen and the other is (CH2)õ-R';
n is 0 or 1 and R' is selected from aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle.
Y is a mono-substituting group selected from H or F; and R1 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl.
Further preferred R1 is a substituted lower alkyl selected from * R9 R
R
where R8, R9 are both methyl, or linked to form a cyclopropyl, cyclobutyl, cyclopentyl or acyclohexyl group;
R10 is (CH2)m-Rii;
m is 0, 1 or 2;
R11 is selected from hydrogen, hydroxyl, lower alkyl, lower alkoxy, aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle, R2 iS H;
R3 iS H;
R5 is a substituted phenyl selected from:
W W W
or .* V 11101 *
=
11011 ;
W is F, Cl or Br;
V is H or F;
R4 is hydrogen;
one of R6 and R7 is hydrogen and the other is (CH2)õ-R';
n is 0 or 1 and R' is selected from aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle.
7 Especially preferred are compounds selected from the group consisting of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide, (2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid dimethylamide, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, (2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2S,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-5-[4-(2-morpholin-4-y1-2-oxo-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile, rac-(25,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-5-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile, rac-(2S,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-5-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydroxy-butyl)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-piperazin-1-yl-ethyl)-amide, (S)-2- { [(2R,3R,4R,5 S)-3 -(3-chloro-pheny1)-4-(4-chloro -pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-amino} -3-methyl-butyric acid methyl ester, (S)-2- {[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-methyl-butyric acid, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclopropylmethyl)-amide, rac-(2R,3R,4R,5S)-3-(3-Chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclobutylmethyl)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl) pyrrolidine-2-carboxylic acid (3,3-dimethyl-buty1)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2,2-dimethyl-propy1)-amide,
8 (2S ,3R,4R,5R)-4-(3- chloro-pheny1)-3 -(4- chloro -pheny1)-2-(2,2- dimethyl-propy1)-5 -((S)-2-hydro xymethyl-pyrro lidine-1- carbonyl) pyrro lidine-3 - carbonitrile, rac-(2R,3R,4R,5 S)-3 -(3 - chloro-pheny1)-4-(4-chloro -pheny1)-4- cyano -542,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 2-(3,4-dimethoxy-phenyl)ethyl amide, (2S ,3S,4S ,5R)-3 -(3-chloro-phenyl)-4-(4- chloro-pheny1)-4- cyan -5 -(2,2-dimethyl-propy1)-pyrro lidine-2- carbo xylic acid ((R)-1-hydroxymethy1-3-methyl-buty1)-amide, rac-(2R,3R,4R,5 S)-3 -(3 - chloro-pheny1)-4-(4-chloro -pheny1)-4- cyano -542,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide, rac-(2R,3 S ,4R,5 S)-3 -(3- chloro -2-fluoro-pheny1)-4-(4- chloro -pheny1)-4-cyano -5 -(2,2- dimethyl-propy1)-pyrro lidine-2-carboxylic acid [2-(cis-2,6-dimethyl-morpho lin-4-y1)-ethyl] -amide, rac-(2R,3R,4R,5 S)-3 -(3 - chloro-pheny1)-4-(4-chloro -pheny1)-4- cyano -5-(2,2- dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-cyclopropyl-ethyl)-amide, rac-(3- { [(2R,3R,4R,5 S)-3 -(3 - chloro-pheny1)-4-(4-chloro -pheny1)-4- cyano -5 -(2,2- dimethyl-propy1)-pyrrolidine-2-carbonyll-amino} -propy1)-carbamic acid tert-butyl ester, rac-(2R,3R,4R,5 S)-3 -(3 - chloro-pheny1)-4-(4-chloro -pheny1)-4- cyano -5-(2,2- dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-amino-propy1)-amide, rac-(2R,3R,4R,5 S)-3 -(3 - chloro-pheny1)-4-(4-chloro -pheny1)-4- cyano -5-(2,2- dimethyl-propy1)-pyrrolidine-2-carboxylic acid [3-(1-acetyl-piperidin-4-ylamino)-propy1]-amide, rac-(2R,3R,4R,5 S)-3 -(3 - chloro-pheny1)-4-(4-chloro -pheny1)-4- cyano -5-isobutyl-pyrro lidine-2-carboxylic acid (3-hydroxy-propy1)-amide, rac-(2R,3R,4R,5R)-5-(3- chloro-pheny1)-4-(4- chloro -pheny1)-4- cyano-3 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide, rac-(2R,3R,4R,5 S)-3 -(3 - chloro-pheny1)-4-(4-chloro -pheny1)-4- cyano -5-(2,2- dimethyl-propy1)-2-methyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide, rac-(2R,3 S ,4R,5 S)-3 -(3- chloro -2-fluoro-pheny1)-4-(4- chloro -pheny1)-4-cyano -5 -cyclop entylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3 S ,4R,5 S)-3 -(3- chloro -2-fluoro-pheny1)-4-(4- chloro -pheny1)-4-cyano -5 -(2,2- dimethyl-propy1)-pyrro lidine-2-carboxylic acid (2-hydro xy-1,1-dimethyl- ethyl)-amide, rac-(2R,3 S ,4R,5 S)-3 -(3- chloro -2-fluoro-pheny1)-4-(4- chloro -pheny1)-4-cyano -5 -(2,2- dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-hydroxy-2,2-dimethyl-propy1)-amide, rac-(2R,3 S ,4R,5 S)-3 -(3- chloro -2-fluoro-pheny1)-4-(4- chloro -pheny1)-4-cyano -5 -(2,2- dimethyl-propy1)-pyrro lidine-2-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl] -amide, rac-(2R,3 S ,4R,5 S)-3 -(3- chloro -2-fluoro-pheny1)-4-(4- chloro -pheny1)-4-cyano -5 -(2,2- dimethyl-propy1)-pyrro lidine-2-carboxylic acid (2-acetylamino-ethyl)-amide,
9 rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-imidazol-1-yl-propy1)-amid, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-4-hydroxy-3-methyl-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid cyclopropylmethoxy-amide, rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide, rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3R,4R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-5-tert-buty1-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyp-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-4-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide, 5 rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-4-(4-fluoro-pheny1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-
10 propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide, rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, (2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny0-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide, rac-(25,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide,
11 rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, (2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide, (2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide,
12 rac-(2R,3 S ,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2-methy1-2-phenyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3R,4R,5 S)-3 -(3 -chloro-5 -fluor -pheny1)-4 -(4-chloro-2-fluoro -pheny1)-4-cyano -5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3 S ,4R,5 S)-4-(4-chloro -2-fluoro-pheny1)-345-chloro -2-(2-hydro xy-etho xy)-phenyl] -4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3 S ,4R,5 S)-4-(4-chloro -2-fluoro-pheny1)-3-(5-chloro -2-metho xy-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac(2R,3R,4R,5 S)-3 -(3-chloro-pheny1)-4-(4-chloro -pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (quino lin-3-ylmethyl)-amide, rac-(2R,3R,4R,5 S)-3 -(3 -chloro-pheny1)-4-(4-chloro -pheny1)-4-cyano -5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 4-hydroxy-benzylamide, rac-(2R,3R,4R,5 S)-3 -(3 -chloro-pheny1)-4-(4-chloro -pheny1)-4-cyano -5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-ethyl-butyl)-amide, rac-4- { [(2R,3 S ,4R,5 S)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino } -piperidine-l-carboxylic acid tert-butyl ester, rac-(2R,3 S ,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic acid, rac-(2R,3 S ,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1-methanesulfonylpiperidin-4-y1)-amide, rac-(2R,3 S ,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1-methyl-carbonyl-piperidin-4-y1)-amide, rac-(2R,3 S ,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1-benzoyl-piperidin-4-y1)-amide, rac-4- { [(2R,3 S ,4R,5 S)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-aminol-p ip eridine-l-carboxylic acid isopropylamide, rac-(2R,35 ,4R,5 S)-3-(3-chloro-2-fluoro -pheny1)-4 -(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [1 -(2-hydro xy-2-methyl-propy1)-1H-pyrazol-3-yl]-amide, chiral 2R,3S ,4R,5 S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbo xylic acid [1 -(2-hydro xy-2-methyl-propy1)-1H-pyrazol-3-yl]-amide,
13 PCT/EP2009/061610 chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propy1)-1H-pyrazo1-3-y1]-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethylpropy1)-pyrrolidine-2-carboxylic acid {1-[2-methy1-2-((R)-1-oxiranylmethoxy)-propy1]-1H-pyrazol-3-y11 -amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid {1-[2-((R)-3-amino-2-hydroxy-propoxy)-2-methyl-propyl] -1H-pyrazol-3-y11 -amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1- {2-[(R)-2-hydroxy-3-(3-hydroxy-propylamino)-propoxy]-2-methyl-propyl} -1H- pyrazol-3-y1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1- {2-[(R)-2-hydroxy-3-(2-hydroxy-1-hydroxymethyl-ethylamino)-propoxy]-2-methyl-propyll-1H-pyrazo1-3-y1)-amide, rac-(2R,35,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethylpropy1)-pyrrolidine-2-carboxylic acid {142-methy1-2-(0)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yll -amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid {142-(0)-3-amino-2-hydroxy-propoxy)-2-methyl-propy1]-1H-pyrazol-3-yll -amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid {142-(0)-2,3-dihydroxy-propoxy)-2-methyl-propy1]-1H-pyrazol-3-yll -amide, of rac-(2R,3S,4R,5S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro -2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid {142-(0)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propy1]-1H-pyrazol-3-y1)-amide, rac- {(S)-3-[2-(3- { R2R,3S,4R,5S)-3 -(3 -chloro-2-fluoro-pheny1)-4-(4-chloro -2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbonyl] -amino} -pyrazol-1 -y1)-1,1-dimethyl-ethoxy] -2-hydroxy-propylamino } -acetic acid, rac-(2R,35,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)pyrrolidine-2-carboxylic acid {142-((S)-2-hydroxy-3-methylamino-propoxy)-2-methyl-propy1]-1H-pyrazol-3-y1 } -amide,
14 rac-(2R,3S,4R ,5S)-3 -(3 -chloro-2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid {1424(R)-3-dimethylamino-2-hydroxy-prop xy)-2-methyl-propyl] -1H-pyrazol-3 -y1)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro -pheny1)-4-(4-chloro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [1 -((R)-2,3-dihydro xy-propy1)-1H-pyrazol-3 -yl] -amide, rac-(2R,3R,4R,5S)-3-(3-chloro -pheny1)-4-(4-chloro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbo xylic acid [1 -(2-hydro xy- ethyl)-1H-pyrazol-3 -yl] -amide, rac-(2R,3R,4R,5S)-3-(3-chloro -pheny1)-4-(4-chloro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-2,3-dihydroxy-propy1)-amide, rac- (2S,35,45,5R)-3-(3 -chloro-pheny1)-4-(4-chloro -pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrro lidine-2-carbo xylic acid (0)-2,3-dihydroxy-propy1)-amide, rac- (2R,3R ,4R ,55)-3 -(3 -chloro-pheny1)-4-(4-chloro -pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrro lidine-2-carbo xylic acid [1 -((R)-2,2-dimethyl- [1,3] dioxo lan-4-ylmethyl)-1H-pyrazol-3 -yl] -amide, rac-(2R,3R,4R,5S)-3-(3-chloro -pheny1)-4-(4-chloro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 2-trifluoromethyl-benzylamide, rac-(2R,3R ,4R ,5S)-3 -(3 -chloro-pheny1)-4-(4-chloro -pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrro lidine-2-carbo xylic acid 4-(2-oxo-pyrrolidin-1-y1)-benzylamide, rac-(2R,3R,4R,5S)-3-(3-chloro -pheny1)-4-(4-chloro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro -pheny1)-4-(4-chloro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-hydroxy-2-hydroxymethyl-propy1)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro -pheny1)-4-(4-chloro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [2-(2-amino-ethoxy)-ethyl]-amide, rac-(2R,3R,4R,5S)-3-(3-chloro -pheny1)-4-(4-chloro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-methanesulfonyl-propy1)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro -pheny1)-4-(4-chloro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-methanesulfonyl-ethyl)-amide, rac-4- { [(2R,3 S ,4R,5 S)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino } -cyclohexylamino-l-carboxylic acid tert-butyl ester, rac-4- { [(2R,3 S ,4R,5 S)-3-(3-chloro-2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino } -trans-cyclohexylamine trifluoro acetic acid salt, rac-4- {[(2R,3S ,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-amino}-trans-cyclo hexyl-N-methanesulfonamide, rac-4- {[(2R,3S ,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-amino}-trans-cyclo hexyl-N-methanesulfonamide, 5 rac-4- {[(2R,3S ,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-amino}-trans-cyclo hexyl-(1,1-dioxo)-2-isothiazo lidine, rac-4- {[(2R,3S ,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-amino}-trans-cyclo hexyl-urea, 10 rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid N-[1-(2-hydroxy ethyl)-piperidin-4-yl]amide, rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-aminoI-piperidine-1-sulfonic acid amide, rac 3- { 4- [(2R,3S ,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-
15 (2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-piperazin-1-y11-acetic acid, rac 3- { 4- [(2R,3S ,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-piperazin-1-y1} - N,N-bis-(2-methoxy-ethyl)-acetamide, rac 3- { 4- [(2R,3S ,4R,5S)-3-(3-Chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-piperazin-1-y1}- N,N-bis-(2-hydroxy-ethyl)-acetamide, rac 3- { 4- [(2R,3S ,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-piperazin-1-y1} - N-( 3-methoxy-propy1)-acetamide, rac 2- {4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-piperazin-1-y1}-acetamide, rac (2S,3R,4S,5R)-4-(3-chloro-2-fluoro-pheny1)-3-(4-chloro-2-fluoro-pheny1)-2-(2,2-dimethyl-propy1)-544-(2-morpholin-4-y1-2-oxo-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile, rac 2- {4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-piperazin-1-y11-N-[2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl]-acetamide, rac 2- {4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro 2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-piperazin-1-y1} -N-((S)-3,4-dihydroxy-buty1)-acetamide,
16 rac {1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-piperidin-4-y1}-acetic acid methyl ester, rac {1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-piperidin-4-y11-acetic acid hydrochloride salt, rac 2- {1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-piperidin-4-y1}-acetamide, rac 2- {1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-y1}-N,N-bis-(2-hydroxy-ethyl)-acetamide, rac 2- {1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro 2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-piperidin-4-y1}-N-(2-hydroxy-ethyl)-N-methyl-acetamide, rac 2- {1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yll -N-(2-hydroxy-propy1)-acetamide, rac {[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -acetic acid tert-butyl ester, rac {[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyTaminol-acetic aid trifluoro acetic acid salt, rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid carbamoylmethyl-amide, { [(2R,3 S,4R,5 S)-3 -(3-chloro -2-fluoro -phenyl)-4-(4-chloro -2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyTamino } -acetic aid trifluoro acetic acid salt, rac 3- {[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-aminol-benzoic acid ethyl ester, rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-carbamoyl-pheny1)-amide, rac 3- {[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino} -benzoic acid tert-butyl ester, rac 3- {[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-aminol-benzoic acid, rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-hydroxymethyl-pheny1)-amide, rac (3- {[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-amino} -propy1)-carbamic acid tert-butyl ester,
17 rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-amino-propy1)-amide, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [3-(aminosulfonyl-amino)-propy1)-amide, rac 2- { [(2R,3 S ,4R,5S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino } -benzoic acid tert-butyl ester, rac 4- { [(2R,3 S ,4R,5S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino } -benzoic acid tert-butyl ester, rac 4- { [(2R,3 S ,4R,5 S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino } -benzoic acid ethyl ester, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-carbamoyl-phenyl)-amide, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-carbamoyl-phenyl)-amide, rac 2- { [(2R,3 S ,4R,5 S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino 1 -benzoic acid ethyl ester, rac 4- { [(2R,3 S ,4R,5 S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-aminol-benzoic acid, rac 2- { [(2R,3 S ,4R,5 S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino}-benzoic acid, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-cyano-pheny1)-amide, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-hydroxy-2-methyl-propy1)-amide, rac 3- { [(2R,3 S ,4R,5 S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino}-benzoic acid 2-hydro xy-2-methyl-propyl ester, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-methanesulfonylamino-pheny1)-amide, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbo xylic acid (1H-tetrazol-5-ylmethyl)-amide, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-ureado-propy1)-amide, rac (2R,3 S,4R,5 S)-3-(3 -chloro-2-fluoro-pheny1)-4 -(4-chloro-2-fluoro -pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-methylsulfanyl-pheny1)-amide,
18 rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-methanesulfonyl-pheny1)-amide, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-methanesulfinyl-pheny1)-amide, 3- { [(2R,3 S,4R,5 S)-3 -(3 -chloro-2-fluoro -pheny1)-4 -(4-chloro-2-fluoro -pheny1)-4-cyano -542,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-aminoI-benzoic acid, (2R,3 S ,4R,5 S)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-carbamoyl-pheny1)-amide, rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2 -fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-y1)-pheny1]-amide, rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2 -fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [4-(1H-tetrazol-5-y1)-pheny1]-amide, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-amino-phenyl)-amide, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-acetylamino-phenyl)-amide, rac 2- { [(2R,3 S ,4R,5 S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-aminol-thiazole-4-carboxylic acid ethyl este,r rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1 ,3 -dio xo-2,3-dihydro -1H-iso indo1-5 -y1)-amide, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (6-oxo-1,6-dihydro-pyridin-3-y1)-amide, (2R,3 S ,4R,5 S)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (6-oxo-1,6-dihydro-pyridin-3-y1)-amide, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-methylsulfanyl-phenyl)-amide, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-methanesulfonyl-phenyl)-amide, 4- { [(2R,3 S,4R,5 S)-3 -(3 -chloro-2-fluoro -pheny1)-4 -(4-chloro-2-fluoro -pheny1)-4-cyano -542,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]aminol-benzoic acid tert-butyl ester, 4- { [(2R,3 S,4R,5 S)-3 -(3 -chloro-2-fluoro -pheny1)-4 -(4-chloro-2-fluoro -pheny1)-4-cyano -542,2-dimethyl-propy1)-pyrro lidine-2-carbonyTaminoI-benzoic acid, 4- { [(25,3R,4 S,5R)-3 -(3 -chloro-2-fluoro -pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -542,2-dimethyl-propy1)-pyrro lidine-2-carbonyTaminoI-benzoic acid,
19 (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-carbamoyl-phenyl)-amide, (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-phenyl)-amide, rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-methanesulfonylamino-phenyl)-amide, rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-trifluoro-methanesulfonylamino-pheny1)-amide, rac (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [3-(1-methy1-1H-tetrazol-5-y1)-phenyl]-amide, rac (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [3-(2-methy1-1H-tetrazol-5-y1)-phenyl]-amide, (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (6-oxo-1,6-dihydro-pyridin-3-y1)-amide, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2 -fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1H-tetrazol-5-y1)-pheny1]-amide, (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2 -fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [4-(1H-tetrazol-5-y1)-pheny1]-amide, rac (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [4-(2-methyl-1H-tetrazol-5-y1)-phenyl]-amide, rac (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [4-(1-methy1-1H-tetrazol-5-y1)-phenyl]-amide, rac 5- tR2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2 -fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-y1)-pheny1]-amide, (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2 -fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-y1)-pheny1]-amide, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-carbamoy1-3-chloro-phenyl)-amide, rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [3-chloro-4-(1H-tetrazol-5-y1)-phenyTamide, rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-fluoro-phenyl)-amide, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-fluoro-pheny1)-amide, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-chloro-pheny1)-amide, 5 rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-chloro-phenyl)-amide, rac 4- { [(2R,3 S ,4R,5S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino } -2-fluoro-benzoic acid tert-butyl ester, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-10 dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-ethylcarbamoy1-3-fluoro-phenyl)-amide, rac 4- { [(2R,3 S ,4R,5 S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino } -2-fluoro-benzoic acid, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (6-methoxy-pyridin-3-y1)-amide, 15 rac 3 -( { [(2R,3 S,4R,5 S)-3-(3-chloro-2-fluoro -pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino}-methyl)-benzoic acid methyl ester, rac 4-( { [(2R,3 S,4R,5 S)-3-(3-chloro-2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-aminol-methyl)-benzoic acid methyl ester, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-
20 dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-chloro-phenyl)-amide, (2R,3 S ,4R,5 S)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-chloro-phenyl)-amide, (2S ,3R,4 S,5R)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-chloro-phenyl)-amide, rac 4- { [(2R,3 S ,4R,5S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino}-2-metho xy-benzo ic acid methyl ester, rac 3 -( { [(2R,3 S,4R,5 S)-3-(3-chloro-2-fluoro -pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino } -methyl)-benzoic acid, rac 4-({[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino } -methyl)-benzoic acid, (2R,3 S ,4R,5 S)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-acetylamino-phenyl)-amide, (2S ,3R,4 S,5R)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-acetylamino-phenyl)-amide,
21 (2R,3 S ,4R,5 S)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-methanesulfonyl-phenyl)-amide, (2S ,3R,4 S,5R)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-methanesulfonyl-phenyl)-amide, rac 4- { [(2R,3 S ,4R,5S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino } -2-methoxy-benzoic acid, rac 5 -bromo-4- { [(2R,3 S,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbonyl] -amino } -2-methoxy-benzoic acid methyl ester, rac 4- { [(2R,3 S ,4R,5 S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino } -2-methyl-benzoic acid methyl ester, rac 2-Chloro -4- { [(2R,3 S ,4R,5 S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbonyl] -amino } -benzoic acid methyl ester, rac 4- { [(2R,3 S ,4R,5 S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino } -2-trifluoromethyl-benzoic acid methyl ester, rac 4- { [(2R,3 S ,4R,5 S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino } -2-methyl-benzoic acid, rac 2-Chloro -4- { [(2R,3 S ,4R,5 S)-3-(3-chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbonyl] -amino } -benzoic acid, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [4-(2H-[1,2,4]triazo1-3-y1)-phenyli-amide, rac (2R,3 S,4R,5 S)-3-(3-chloro -2-fluoro -pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbo xylic acid [4-(5 -o xo -2,5 -dihydro -1 H- [1,2,4]tiazol-3 -y1)-phenyl]-amide, rac-(2R,3 S,4R,5 S)-3 -(5-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3 S,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2-cyclopropy1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, (2R,3 S ,4R,5 S)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2-cyclopropy1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3 S,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -3-methyl-p heny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3 S,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide,
22 rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methoxycarbony1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethy1-2-methyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethy1-2-hydroxymethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide,
23 (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[4-(2-hydroxy-ethoxy)-2,2-dimethyl-butyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide, rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide, rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-methanesulfonylamino-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-5-(4-benzoylamino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide,
24 rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-y1)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propy1]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-piperidin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(tetrahydro-pyran-4-y1)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-penty1)-amide, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-penty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-penty1)-amide , (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-penty1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-penty1)-amide, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-penty1)-amide, rac-(2S,3R,4S,5R)-4-(3-cloro-2-fluoro-pheny1)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propy1)-5-(3-hydroxy-azetidine-1-carbonyl)-pyrrolidine-3-carbonitrile, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propy1)-1H-pyrazo1-3-y11-amide, (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propy1)-1H-pyrazo1-3-y11-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propy1)-1H-pyrazo1-3-y1]-amide, 10 (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propy1)-1H-pyrazo1-3-y1]-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid amide, 15 rac-6-{ [(2R,3 S ,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-amino}-nicotinic acid methyl ester, of rac-6- {[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbony11-aminol-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide, 20 rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (6-acetylamino-pyridin-3-y1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1-methy1-2-oxo-1,2-dihydro-pyridin-4-y1)-amide,
25 (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1-methy1-2-oxo-1,2-dihydro-pyridin-4-y1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-y11-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid (1-methy1-2-oxo-1,2-dihydro-pyridin-4-y1)-amide, rac-5- { [(2R,3 S ,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-amino}-furan-2-carboxylic acid methyl ester,
26 rac-5- { [(2R,3 S ,4R,5 S)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino}-furan-2-carbo xylic acid, rac-5- { [(2R,3 S ,4R,5 S)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino}-furan-2-carbo xylic acid amide, rac-(2R,3 S,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (6-chloro-pyridazin-3-y1)-amide, rac-(2R,3 S,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-methyl-pyridin-3-y1)-amide, rac-(2R,3 S,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]-amide, (2R,3 S ,4R,5 S)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]-amide, rac-5- { [(2R,3 S ,4R,5 S)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino}-thiophene-2-carboxylic acid methyl ester, rac-5- { [(2R,3 S ,4R,5 S)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino}-thiophene-2-carbo xylic acid, 5- { [(2R,3 S,4R,5 S)-3 -(3 -chloro-2-fluoro -pheny1)-4 -(4-chloro-2-fluoro -pheny1)-4-cyano -5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyTaminol-thiophene-2-carbo xylic acid rac-(2R,3 S,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-methoxy-pyridin-4-y1)-amide, rac-(2R,3 S,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-hydroxy-pyridin-4-y1)-amide, rac-(2R,3 S,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-acetyl-phenyl)-amide, rac-(2R,3 S,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [4-(2-bromo-acetyl)-phenyl]amide, rac-(2R,3 S,4R,5 S)-3 -(3-chloro -2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [4-(2- dimethylamino-acetyl)-phenyl]-amide, rac-(5- { [(2R,3S,4R ,5S)-3 -(3 -chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino1-4H-[1,2,4]triazo1-3-y1)-acetic acid, rac-(3- { [(2R,3S,4R ,5S)-3 -(3 -chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-aminoI-pyrazol-1 -y1)-acetic acid, rac-(2R,3S,4R ,5S)-3 -(3 -chloro-2-fluoro-pheny1)-4-(4-chloro -2-fluoro -pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1H-imidazo1-4-ylmethyl)-amide,
27 rac-(2S,3R,4S,5R)-4-(3-chloro-2-fluoro-pheny1)-3-(4-chloro-2-fluoro-pheny1)-2-(2,2-dimethyl-propyl)-5-(2-oxa-6-aza-spiro[3.3]heptane-6-carbony1)-pyrrolidine-3-carbonitrile, rac-1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-azetidine3-carboxylic acid, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1-carbamoylmethy1-1H-pyrazo1-3-y1)-amide, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propy1)-1H-pyrazo1-3-y1]-amide, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfonylamino-propy1)-amide, chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {142-((S)-3-dimethylamino-2-hydroxy-prop xy)-2-methyl-propyl] -1H-pyrazol-3 - yll -amide, chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid {142-(0)-3-dimethylamino-2-hydroxy-prop xy)-2-methyl-propyl] -1H-pyrazol-3 - yll -amide, rac-1- {[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino}-cyclopropane carboxylic acid, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(4-hydroxy-piperidin-4-ylmethyl)-1H-pyrazo1-3-y1]-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-acetyl-thiophen-3-y1)-amide, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-carbamoyl-thiophen-3-y1)-amide, rac- (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [14(S)-3-dimethylamino-2-hydroxy-propy1)-1H-pyrazol-3-y1]-amide, rac-4- { [(2R,3 S ,4R,5 S)-3-(3 -chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(1-methyl- cyclo hexylmethyl)-pyrro lidine-2-carbonyl] -aminol-benzoic acid, rac-4- { [(2R,3 S ,4R,5 S)-3-(5 -chloro -2-fluoro-pheny1)-4-(4-chloro-2-fluoro -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino}-benzoic acid methyl ester,
28 rac-4- {[(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino}-benzoic acid, rac-4- {[(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-amino}-benzoic acid methyl ester, rac-4- {[(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino}-benzoic acid, rac-4- {[(2R,3R,4R,5 S)-3 -(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyli-amino}-benzoic acid methyl ester, of rac-4- { [(2R,3R,4R,5 S)-3 -(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-1 0 dimethyl-propy1)-pyrro lidine-2-carbonyl]-amino 1 -benzoic acid, rac-4- {[(2R,3 S ,4R,5 S)-3-(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyli-amino}-benzoic acid methyl ester, rac-4- {[(2R,3 S ,4R,5 S)-3-(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbonyl]-amino 1 -benzoic acid, rac-4- {[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carbonyl]-aminoI-benzoic acid methyl ester and rac- [4-(3- { [(2R,3 S ,4R,5 S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrro lidine-2-carbonyll-amino} -pyrazol- 1 -ylmethyl)-4-hydroxy-piperidin-1-y11-acetic acid.
In the specification where indicated the various groups may be substituted by 1-5 or, preferably, 1-3 substituents independently selected from the group consisting of lower alkyl, lower-alkenyl, lower-alkynyl, dioxo-lower-alkylene (forming e.g. a benzodioxyl group), halogen, hydroxy, CN, CF3, NH2, N(H, lower-alkyl), N(lower-alky1)2, aminocarbonyl, carboxy, NO2, lower-alkoxy, thio-lower-alkoxy, lower-alkylsufonyl, amino sulfonyl, lower-alkylcarbonyl, lower-alkylcarbonyloxy, lower-alkoxycarbonyl, lower-alkyl-carbonyl-NH, fluoro-lower-alkyl, fluoro-lower-alkoxy, lower-alkoxy-carbonyl-lower-alkoxy, carboxy-lower-alkoxy, carbamoyl-lower-alkoxy, hydroxy-lower-alkoxy, NH2-lower-alkoxy, N(H, lower-alkyl)-lower-alkoxy, N(lower-alky1)2-lower-alkoxy, lower-alkyl-l-oxiranyl-lower-alkoxy-lower-alkyl, 2-oxo-pyrrolidin-1-y1, (1,1-dioxo)-2-isothiazolidine, 3-lower-a1kyl sulfinyl, a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heteroaryl ring, trifluoro-lower-alkylsulfonylamino-aryl, lower-alkyl sulfonylaminocarbonyl, lower-alkyl sulfonylaminocarbonyl-aryl, hydroxycarbamoyl-phenyl, benzyloxy-lower-alkoxy, mono- or di-lower alkyl substituted amino-sulfonyl and lower-alkyl which can optionally be substituted with
In the specification where indicated the various groups may be substituted by 1-5 or, preferably, 1-3 substituents independently selected from the group consisting of lower alkyl, lower-alkenyl, lower-alkynyl, dioxo-lower-alkylene (forming e.g. a benzodioxyl group), halogen, hydroxy, CN, CF3, NH2, N(H, lower-alkyl), N(lower-alky1)2, aminocarbonyl, carboxy, NO2, lower-alkoxy, thio-lower-alkoxy, lower-alkylsufonyl, amino sulfonyl, lower-alkylcarbonyl, lower-alkylcarbonyloxy, lower-alkoxycarbonyl, lower-alkyl-carbonyl-NH, fluoro-lower-alkyl, fluoro-lower-alkoxy, lower-alkoxy-carbonyl-lower-alkoxy, carboxy-lower-alkoxy, carbamoyl-lower-alkoxy, hydroxy-lower-alkoxy, NH2-lower-alkoxy, N(H, lower-alkyl)-lower-alkoxy, N(lower-alky1)2-lower-alkoxy, lower-alkyl-l-oxiranyl-lower-alkoxy-lower-alkyl, 2-oxo-pyrrolidin-1-y1, (1,1-dioxo)-2-isothiazolidine, 3-lower-a1kyl sulfinyl, a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heteroaryl ring, trifluoro-lower-alkylsulfonylamino-aryl, lower-alkyl sulfonylaminocarbonyl, lower-alkyl sulfonylaminocarbonyl-aryl, hydroxycarbamoyl-phenyl, benzyloxy-lower-alkoxy, mono- or di-lower alkyl substituted amino-sulfonyl and lower-alkyl which can optionally be substituted with
29 halogen, hydroxy, NH2, N(H, lower-alkyl) or N(lower-alky1)2.. Preferred substituents for the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle rings are halogen, lower alkoxy, lower alkyl, hydroxycarbonyl, carboxy, carboxy lower alkoxy, oxo and CN. Preferred substituents for alkyl are alkoxy and N(lower alky1)2.
The term "alkyl" refers to straight- or branched-chain saturated hydrocarbon groups having from 1 to about 20 carbon atoms, including groups having from 1 to about 7 carbon atoms. In certain embodiments, alkyl substituents may be lower alkyl substituents. The term "lower alkyl" refers to alkyl groups having from 1 to 6 carbon atoms, and in certain embodiments from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
As used herein, "cycloalkyl" is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, any ring of which being saturated, and the term "cycloalkenyl" is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, with at least one ring thereof being partially unsaturated. Preferably, "cycloalkyl" as used herein consists of 3 to 10 carbon atoms and "cycloalkenyl" of 5 to 10 carbon atoms. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicycloalkyls, including bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds. Examples of cycloalkenyls include, but are not limited to, cyclopentenyl or cyclohexenyl.
The term "alkenyl" as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one double bond and having 2 to 6, preferably 2 to 4 carbon atoms.
Examples of such "alkenyl group" are vinyl, ethenyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl- 1-butenyl, 3-methy1-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
The term "alkynyl" as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one triple bond and having 2 to 6, preferably 2 to 4 carbon atoms.
Examples of such "alkynyl group" are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
The term "halogen" as used in the definitions means fluorine, chlorine, bromine, or iodine, 5 preferably fluorine and chlorine.
"Aryl" means a monovalent, monocyclic or bicyclic, aromatic carbocyclic hydrocarbon radical, preferably a 6-10 member aromatic ring system. Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl. Where the aryl group is bicyclic 10 a preferred group is 1,3-dioxo-2,3-dihydro-1H-isoindo1-5-y1 group.
"Heteroaryl" means an aromatic, preferably 5 to 10 membered, mono- or bicyclic aromatic hydrocarbon, wherein 1 to 4, preferably 1 to 3 carbon atoms are replaced by a hetero atom selected from nitrogen, oxygen or sulfur atom. Preferred heteroaryl groups include, but are not 15 limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazole substituted or unsubstituted triazoly1 and substituted or unsubstituted tetrazolyl.
In the case of aryl or heteroaryl which are bicyclic it should be understood that one ring may be 20 aryl while the other is heteroaryl and both being substituted or unsubstituted. In case of bicyclic ring systems the two rings can be fused (like i.e. in naphthyl) or linked via a single bond (like i.e.
in biphenyl).
"Heterocycle" or "heterocyclic ring"means a substituted or unsubstituted 5 to 10-, preferably 5 to 25 8 membered, mono- or bicyclic, non-aromatic hydrocarbon, wherein 1 to 3 carbon atoms are replaced by a hetero atom selected from nitrogen, oxygen or sulfur atom.
Examples include pyrrolidin-2-y1; pyrrolidin-3-y1; piperidinyl; morpholin-4-y1 and the like which in turn can be substituted. "Hetero atom" means an atom selected from N, 0 and S.
The term "alkyl" refers to straight- or branched-chain saturated hydrocarbon groups having from 1 to about 20 carbon atoms, including groups having from 1 to about 7 carbon atoms. In certain embodiments, alkyl substituents may be lower alkyl substituents. The term "lower alkyl" refers to alkyl groups having from 1 to 6 carbon atoms, and in certain embodiments from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
As used herein, "cycloalkyl" is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, any ring of which being saturated, and the term "cycloalkenyl" is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, with at least one ring thereof being partially unsaturated. Preferably, "cycloalkyl" as used herein consists of 3 to 10 carbon atoms and "cycloalkenyl" of 5 to 10 carbon atoms. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicycloalkyls, including bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds. Examples of cycloalkenyls include, but are not limited to, cyclopentenyl or cyclohexenyl.
The term "alkenyl" as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one double bond and having 2 to 6, preferably 2 to 4 carbon atoms.
Examples of such "alkenyl group" are vinyl, ethenyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl- 1-butenyl, 3-methy1-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
The term "alkynyl" as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one triple bond and having 2 to 6, preferably 2 to 4 carbon atoms.
Examples of such "alkynyl group" are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
The term "halogen" as used in the definitions means fluorine, chlorine, bromine, or iodine, 5 preferably fluorine and chlorine.
"Aryl" means a monovalent, monocyclic or bicyclic, aromatic carbocyclic hydrocarbon radical, preferably a 6-10 member aromatic ring system. Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl. Where the aryl group is bicyclic 10 a preferred group is 1,3-dioxo-2,3-dihydro-1H-isoindo1-5-y1 group.
"Heteroaryl" means an aromatic, preferably 5 to 10 membered, mono- or bicyclic aromatic hydrocarbon, wherein 1 to 4, preferably 1 to 3 carbon atoms are replaced by a hetero atom selected from nitrogen, oxygen or sulfur atom. Preferred heteroaryl groups include, but are not 15 limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazole substituted or unsubstituted triazoly1 and substituted or unsubstituted tetrazolyl.
In the case of aryl or heteroaryl which are bicyclic it should be understood that one ring may be 20 aryl while the other is heteroaryl and both being substituted or unsubstituted. In case of bicyclic ring systems the two rings can be fused (like i.e. in naphthyl) or linked via a single bond (like i.e.
in biphenyl).
"Heterocycle" or "heterocyclic ring"means a substituted or unsubstituted 5 to 10-, preferably 5 to 25 8 membered, mono- or bicyclic, non-aromatic hydrocarbon, wherein 1 to 3 carbon atoms are replaced by a hetero atom selected from nitrogen, oxygen or sulfur atom.
Examples include pyrrolidin-2-y1; pyrrolidin-3-y1; piperidinyl; morpholin-4-y1 and the like which in turn can be substituted. "Hetero atom" means an atom selected from N, 0 and S.
30 "Alkoxy, alkoxyl or lower alkoxy" refers to any of the above lower alkyl groups attached to an oxygen atom. Typical lower alkoxy groups include methoxy, ethoxy, isopropoxy or propoxy, butyloxy and the like. Further included within the meaning of alkoxy are multiple alkoxy side chains, e.g. ethoxy ethoxy, methoxy ethoxy, methoxy ethoxy ethoxy and the like and substituted alkoxy side chains, e.g., dimethylamino ethoxy, diethylamino ethoxy, dimethoxy-phosphoryl methoxy and the like.
31 "Pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
"Pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, trifluoro acetic acid and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456- 1457.
The compounds of formula I and II as well as their salts that have at least one asymmetric carbon atom may be present as racemic mixtures or different stereoisomers. The various isomers can be isolated by known separation methods, e.g., chromatography.
Compounds disclosed herein and covered by formula I and II above may exhibit tautomerism or structural isomerism. It is intended that the invention encompasses any tautomeric or structural isomeric form of these compounds, or mixtures of such forms, and is not limited to any one tautomeric or structural isomeric form depicted in the formulas above.
The compounds of the present invention are useful in the treatment or control of cell proliferative disorders, in particular oncological disorders. These compounds and formulations containing said compounds may be particularly useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors.
"Pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, trifluoro acetic acid and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456- 1457.
The compounds of formula I and II as well as their salts that have at least one asymmetric carbon atom may be present as racemic mixtures or different stereoisomers. The various isomers can be isolated by known separation methods, e.g., chromatography.
Compounds disclosed herein and covered by formula I and II above may exhibit tautomerism or structural isomerism. It is intended that the invention encompasses any tautomeric or structural isomeric form of these compounds, or mixtures of such forms, and is not limited to any one tautomeric or structural isomeric form depicted in the formulas above.
The compounds of the present invention are useful in the treatment or control of cell proliferative disorders, in particular oncological disorders. These compounds and formulations containing said compounds may be particularly useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors.
32 Consequently, as a further embodiment according to the present invention there are provided the compounds according to formula I and II for use as medicaments, in particular for the use as medicaments in the treatment of cancer, more particular solid tumors, and most particularly breast, colon, lung and prostate tumors.
A therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art.
Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration; it may be given as continuous infusion.
Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, as well as the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of a formula I compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately
A therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art.
Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration; it may be given as continuous infusion.
Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, as well as the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of a formula I compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately
33 bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, sachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.
"Effective amount" means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
"IC50" refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity. IC50 can be measured, inter alia, as is described subsequently.
The present invention provides methods for the synthesis of pyrrolidine-2-carboxamide. The compounds of the invention can be prepared by processes known in the art.
Suitable processes for synthesizing these compounds are provided in the examples.
Compounds of this invention can be synthesized according to the following general schemes.
The key transformation is a convergent [2+3] cylcoaddition of emine II and activated olefin III
to generate pyrrolidine-3-carbonitrile compounds IV in a stereoselective and efficient manner.
The starting materials are either commercially available or can be synthesized by methods known to those of ordinary skill in the art. Preparations of intermediates II
and III are illustrated in Scheme 1 and 2. In general an appropriately selected aldehyde or ketonecan be reacted with glycine tert-butyl ester or glycine methyl ester to generate imine II and were used as a crude product (Scheme 1).
Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, sachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.
"Effective amount" means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
"IC50" refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity. IC50 can be measured, inter alia, as is described subsequently.
The present invention provides methods for the synthesis of pyrrolidine-2-carboxamide. The compounds of the invention can be prepared by processes known in the art.
Suitable processes for synthesizing these compounds are provided in the examples.
Compounds of this invention can be synthesized according to the following general schemes.
The key transformation is a convergent [2+3] cylcoaddition of emine II and activated olefin III
to generate pyrrolidine-3-carbonitrile compounds IV in a stereoselective and efficient manner.
The starting materials are either commercially available or can be synthesized by methods known to those of ordinary skill in the art. Preparations of intermediates II
and III are illustrated in Scheme 1 and 2. In general an appropriately selected aldehyde or ketonecan be reacted with glycine tert-butyl ester or glycine methyl ester to generate imine II and were used as a crude product (Scheme 1).
34 O
0,O,R R-"'N
RC---NH R1 R2 2 3 ),I1 Reagents and conditions: R is tert-butyl or methyl (1) If R1 or R2 is H, CH2C12, room temperature, overnight;
(2) If R1 and R2 are both not H, ethanol, 100 oC, 48 h;
Scheme 1 An intermediate of formula III can be made from a base-catalyzed condensation reaction of appropriately selected substituted-phenyl acetonitrile and aldehyde The reaction proceedes in a highly stereoselective manner with Z-isomer as the major or exclusive product.
Y 401 `1%1 + R)LR
X X
Reagents and conditions:
If R5 is H, aq. NaOH, iPrOH, room temperature, 5 min or Na0Me, Me0H, 50 C, 3 h Scheme 2 As illustrated in Scheme 3, pyrrolidine of formula IV can be made from intermediates II and III
by a convergent 1,3-dipolar cylcoaddition reaction mediated by lewis acid AgF
and triethylamine.
The [2+3] cycloaddition reactions of azomethine ylides 1,3-dipoles with olefinic dipolarphiles to form pyrrolidine ring formation have been described in published procedures including Jorgensen, K. A. et al (Org. Lett. 2005, Vol 7, No. 21, 4569-4572), Grigg, R.
et al (Tetrahedron, 1992, Vol 48, No. 47, 10431-10442; Tetrahedron, 2002, Vol 58, 1719-1737), Schreiber, S. L. et al (J. Am. Chem. Soc., 2003, 125, 10174-10175), and Carretero, J. C. et al (Tetrahedron, 2007, 63, 6587-6602).. Compounds IV is subsequently converted to acid V followed by amide formation with various amines using HATU as the coupling reagent to give the compounds of formula I. The amide formation from V to I can also be achieved under other conditions using EDCI and HOBt or oxalyl chloride as the coupling reagent to activate the acid V.
P\
0 0- R5 R4 N , õI R a RR4 R3 N + ). R
..'"i\T _______________________________________________________ Y 401 N1 X X
II III IV
N
b R4 N
R2 C R4 N , R5 im.
x Ri R5 -1'2 Y 0 \ NRl Y 0 \X
X N
X
V I
Reagents and conditions:
a. AgF, NE-t2, CH2C12 or C1CH2CH2C1, rt, 18 h;
b. 1) If R is tert-butyl, conc. H2SO4; or TFA, CH2C12, rt, 18 h;
or 2) If R is methyl, NaOH or Li0H, H20 and Me0H and THF, rt, 18 h;
c. HNR6R7, HATU, iPr2NEt, CH2C12, rt, 18 h Scheme 3 10 The process according to scheme 3 forms a further embodiment according to the present invention.
The pyrrolidine compounds I, IV, V are prepared initially as a racemic mixture and can be chirally separated using chiral Super Fluid Chromatography (SFC) or chiral HPLC or chiral 15 column chromatography. For example, racemic mixture of compound Ia and Ia' can be readily resolved into two optically pure or enriched chiral enantiomers by separation using chiral Super Fluid Chromatography (SFC). (Scheme 4).
R
R R
R
N¨R7 i 6 N¨R N¨IoR7 R
0 = 3 N¨R7 R 7 0 Z 3 0 a, . ' 11 1 =::. H
0=1.. R3H ' H R4 N
R
Re,. N.0 R2 + R5,4...
_...\,., N chiral separationR.4,µ R
N
' . ' R
, R 5 =õ== Ri ...0 \ 1 y N x X
X
la la' la la' racemic mixture chiral chiral Scheme 4 Examples The compounds of the present invention may be synthesized according to known techniques. The following examples and references are provided to aid the understanding of the present invention, the true scope of which is set forth in the appended claims.
Example la Preparation of intermediate [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester f)() N
M. W. 213.32 C 1 2H23N0 2 A mixture of glycine tert-butyl ester ( Alfa) (2.71 g, 20.0 mmol) and 3,3-dimethyl-butyraldehyde (Alfa) (2.21 g, 21.0 mmol) in CH2C12 (50 mL) was stirred at rt overnight. The reaction mixture was concentrated and the residue was dried in vacuo to give [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (4.29 g, 100%) as colorless oil which was used in the next step without further purification.
Example lb Preparation of intermediate (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile ci 40 c, '1\1 R05302754-000 CI
CI
5 M. W. 274.2 C15H9C12N
Method A.
To a solution of 4-chlorobenzyl cyanide (5.62 g, 4.00 mmol) and 3-chloro-benzaldehyde (Aldrich) (6.06 g, 4.00 mmol) in iPrOH (250 mL) was added 4 N NaOH (5 mL) dropwise at rt and the reaction mixture was stirred at rt for 10 min to give a white suspension. The solid was 10 filtered and washed with water and iPrOH and then dried overnight in vacuum to give (Z)-3-(3-chloro-pheny1)-2-(4-chloro-phenyl)-acrylonitrile (9.33 g, 85.1%) as a white powder which was used in the next step without further purification.
Method B.
15 To a solution of 4-chlorobenzyl cyanide (Aldrich) (4.5 g, 30 mmol) and 3-chloro-benzaldehyde (Aldrich) (4 g, 29 mmol) in methanol (150 mL) was slowly added a methanolic solution (Aldrich, 25 wt.%) of sodium methoxide (10 mL, 44 mmol). The reaction mixture was heated and stirred at 50 C for 3 h. The mixture became cloudy, and was cooled to room temperarure and filtered.
The white precipitate was washed with water, cold methanol, and then dried in vacu to give the 20 first batch of desired product (5.5 g). The filtrate was concentrated, diluted with water, neutralized by aqueous HC1 solution to "pH" 7, then extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac;hexanes = 1;20, then 1:10) to give the second batch of the desired product (1.6 g).The two batches were combined to give (Z)-3-(3-chloro-pheny1)-2-(4-chloro-25 phenyl)-acrylonitrile as a white powder (7.1 g, 88%).
1-11-0/1S (ES--) Calcd for C15H9C12N Psi Ft 273.0112; found: 273.0113.
Example le Preparation of intermediate rac-(2R,3R,4R,55)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI (:).,0?(' M. W. 487.5 C27H32C12N202 To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (4.26 g, 20.00 mmol) and (Z)-3-(3-chloro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile (5.48 g, 20.00 mmol) in C1CH2CH2C1 (100 mL) were added triethyl amine (4.2 g, 40.00 mmol) and AgF
(2.53 g, 20.00 mmol) in one portion. The mixture was stirred at rt overnight. The mixture was then quenched with sat. NH4C1 and extracted with CH2C12. The organic phase was separated, filtered through Celite and dried over Na2SO4. The mixture was then separated and concentrated.
The residue was triturated with Et0Ac and nHexane, and the precipitates were collected by filtration and the mother liquid was concentrated and further purified by flash column (Si02, 1-20% of Et0Ac in hexanes) to give rac-(2R,3R,4R,55)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester (6.65 g, 68.2%; FIRMS (ES) miz Cala' for C27H32C12N202 + H [(M+H) ]: 4.7. 1914, found: 487 1910) and rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (0.86 g, 8.8%).
HR.N4S (ES') rah Ca[cd for C27H32C12N202 F [(1\141-1)']: 487.1014, found:
487.1910).
Example ld Preparation of intermediate rac-(2R,3R,4R,55)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid Cl c,OH
= NH
CI
M. W. 431.4 C23H24C12N202 A solution of rac-(2R,3R,4R,55)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (3.78 g, 7.75 mmol) in conc.
H2504 (20 mL) was stirred at rt for 2 hrs. The mixture was then poured into ice and extracted with Et0Ac. The organic phase was separated, dried over Na2SO4, and concentrated. The residue was then triturated with Et0Ac and nHexane and the precipitates were collected by filtration and washed with ether to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3.60 g, 100%) as a white solid which was used in the next step without further purification:11RMS ( ES ') miz, Caled for C23H24C12N202 I
[(1\4 11)1: 431.1288, found: 431.1287.
Example le Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide Cl=
NH
CI-Cw"
M. W. 543.5 C29H36C12N402 A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol), 2-morpholin-4-yl-ethylamine (36.0 mg, 0.28 mmol), 2-(7-azabenzotriazo1-1-y1)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2C12 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by Si02 flash column (20-100% of Et0Ac in Hexanes) to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (60.5 mg, 86.4%) as a white amorphous.
H RAS (ES') Trilz. Calcd. for C29H36C12N402 1--1 [0,1-F-I-1)']; 543.2288, found: 523.2284.
Example lf Preparation of (2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide Cl Of = NH
,sµ
M. W. 543.5 C29H36C12N402 The racemic product obtained above (Example le, 45 mg) was further separated by SFC chiral column to give-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (13.1 mg, 29.1%) and (2S,3S,4S,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethylpropy1)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (14.6 mg, 32.4%).
Example 2 5 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid dimethylamide CI N
0.e NH
µµN
CI
M. W. 458.4 C23H29C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-10 pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example ld was reacted with dimethylamine (1.0 M in THF, 2 mL), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid dimethyl amide (57.8 mg, 90.0 %).
15 HRIVIS (ES-) mlz Cated fig C25H29C12N302 H [(1\1+H)-1: 458.1761, found:
458.1757.
Example 3a Preparation of intermediate 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine 0¨ft 20 M. W. 145.20 C7H15NO2 Step A.
To a solution of (4S)-(+)-4-(2-hydroxyethyl)-2,2-dimethy1-1,3-dioxolane (Aldrich) (21.1 g, 0.14 mol) and triethylamine (40 mL, 0.28 mol) in dichloromethane (250 mL) at 0 C
was added methanesulfonyl chloride (13.4 mL, 0.17 mol) dropwise. The reaction mixture was stirred at 0 C
25 for 1.5 h, then water was added. The organic layer was separated, washed with water, brine, dried over MgSO4, concentrated to give methanesulfonic acid 2-((S)-2,2-dimethy141,3]dioxolan-4-y1)-ethyl ester as a yellow oil (31.7 g, 98%).
Step B.
30 To a solution of methanesulfonic acid 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl ester (31.7 g, 0.14 mol) in N,N-dimethylformamide (200 mL) was added NaN3 (46 g, 0.71 mol).
The reaction mixture was stirred at room temperature for 70 h. Then the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine several times, dried over MgSO4, concentrated to give (S)-4-(2-azido-ethyl)-2,2-dimethyl-[1,3]dioxolane as a yellow oil (21.3 g, 88%).
Step C.
A suspension of (S)-4-(2-azido-ethyl)-2,2-dimethyl-[1,3]dioxolane as a yellow oil (18.7 g, 0.11 mol) and Pt02 (2.5 g) in ethyl acetate (100 mL) was vigorously shaken in a Parr under atmosphere of H2 (50 psi) for 18 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine as a colorless oil (14 g, 88%).
Example 3h Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Cl NH OH
\ N
CI
M. W. 518.5 C27H33C12N303 A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (431.4 mg, 1.00 mmol) prepared in Example ld, 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (217.5 mg, 1.5 mmol), HATU
(570.30 mg, 1.50 mmol) and iPr2NEt (258.6 mg, 2.00 mmol) in CH2C12 (20 mL) was stirred at rt for 1 hour.
The mixture was then diluted with CH2C12 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and the residue was treated with PPTS (cat) in Me0H (20 mL) at 120 C for 5 min with CEM
microwave reactor.
The reaction mixture was concentrated and the residue was diluted with Et0Ac and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4.
The mixture was then concentrated and purified by Si02 flash column (5% of Me0H in Et0Ac) to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (450.0 mg, 86.7%) as a white amorphous.
tIRMS (ES--) C.aled {by C27H33C12N303-t 11 [1M 518.1972, found:
518.1970.
Example 3c Preparation of (2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide Cl CI
M. W. 518.5 C27H33C12N303 The racemic product obtained above (Example 3b, 450.0 mg) was further separated by SFC
chiral column to give (2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (178.6 mg, 34.4%) and (2S,3S,45,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (159.8 mg, 30.8%).
Example 4 Preparation of rac-(2S,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-544-(2-morpholin-4-y1-2-oxo-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile ci N
NH CO) C
I
M. W. 626.6 C35H41C12N503 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example ld was reacted with 1-morpholin-4-y1-2-piperazin-1-yl-ethanone (65.0 mg, 0.30 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-5-[4-(2-morpholin-4-y1-2-oxo-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile (45.5 mg, 51.9 %).
FIRMS (ES ')1:11/Z Calcd for C35H41C12N503-:- H [(1'+H)1: 626.2659, found:
626.2654.
Example 5 Preparation of rac-(2S,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propy1)-544-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile 0,,k) w NH
=µµ
CI
M. W. 610.6 C33H41C12N502 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example ld was reacted with 2-piperazin-1-y1-1-pyrrolidin-1-yl-ethanone (65.0 mg, 0.33 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-Chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-5-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazine-l-carbonyl]-pyrrolidine-3-carbonitrile (60.5 mg, 70.8 %).
RAS (ES') atiz Caticd fbr C33H41C12N502-i- 11 )']: 610.271 0, found:
610.2708.
Example 6 Preparation of rac-(2S,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-544-(2-hydroxy-ethyl)-piperazine-1-carbonyll-pyrrolidine-3-carbonitrile cl 0,Nõ) NH
Cl' M. W. 543.5 C29H36C12N402 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example ld was reactod with 2-piperazin-1-yl-ethanol (65.0 mg, 0.50 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propy1)-5-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile (48.3 mg, 63.5 %).
HRIMS (ES') libiZ Cala' for C29H36C12N402-i- H [(M-F-H) ]: 543.2288, found:
543.2284.
Example 7 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-hydroxy-butyl)-amide Cl NH
= NH
CI
M. W. 502.4 C27H33C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example ld was reacted wit h 4-methylamino-butan-1-ol (44.5 mg, 0.50 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydroxy-butyl)-amide (30.5 mg, 43.4 %). FIRMS (ES') m/z Calcd tbr C27H33C12N302+11 [(M+I-I) j:
502.2023, found:
502.2020.
Example 8 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide CI
= NH LJ
Cl' M. W. 527.5 C29H36C12N40 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (82.2 mg, 0.20 mmol) prepared in Example ld was reacted with 2-pyrrolidin-1-yl-ethylamine (34.2 mg, 0.30 mmol), HATU (76.0 mg, 0.20 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (50.6 mg, 64.0 %). FIRMS (ES' ) Calcd for C29H36C12N40 +H [( M I 101: 527.2339, found: 527.2338.
Example 9 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-piperazin-1-yl-ethyl)-amide CI
NH
CI
5 M. W. 542.6 C29H37C12N50 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (82.2 mg, 0.20 mmol) prepared in Example ld was reacted with 2-piperazin-1-yl-ethylamine (38.7 mg, 0.30 mmol), HATU (76.0 mg, 0.20 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in 10 CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-piperazin-1-yl-ethyl)-amide (45.9 mg, 58.0 %). HRIAS (ES) rn/z Calcd for C29H37C12N50 +H [(M+H)+]:
542.2448, found: 542.24 zi 5 .
15 Example 10a Preparation of (S)-2- {[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyTamino1-3-methyl-butyric acid tert-butyl ester ci - NH3_ µN
M. W. 586.6 C32H41C12N303 20 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (215.7 mg, 0.50 mmol) prepared in Example ld was reacted with (S)-2-amino-3-methyl-butyric acid tert-butyl ester (125.4 mg, 0.60 mmol), HATU (210.1.0 mg, 0.60 mmol) and iPr2NEt (129.3 mg, 1.00 mmol) in CH2C12 (5 mL) at rt overnight to give (S)-2-1[(2R,3R,4R,5S)-3-(3-chloro-25 pheny1)-4-(4-chloro -pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrro lidine-2-carbonyl]-aminoI-3-methyl-butyric acid tert-butyl ester (95.0 mg, 32.4 %) after column separation. FIRMS (.[S) rniz Calcd for C32H41C12N303+14 [(NI+H)1: 586.2602, found: 586.2598.
Example 10b Preparation of (S)-2- [(2S,3S,4S ,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-aminoI-3-methyl-butyric acid tert-butyl ester b 0 NH y_ µ' CI N
M. W. 586.6 C32H41C12N303 Column separation from the above example (Example 10a) gave (S)-2-{[(2S,3S,4S,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyll-amino}-3-methyl-butyric acid tert-butyl ester (98.0 mg, 33.4 %).
HRMS (ES) ratz Calcd for C32H41 Cl2N303 H [(M+H)']: 586.2601, found: 586.2598, Example 10c Preparation of (S)-2- { [(2R,3R,4R,5 S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-aminoI-3-methyl-butyric acid methyl ester CI NH
=NHo R
M. W. 544.5 C29H35C12N303 Column separation from the above example (Example 10a) gave a mixture of (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyll-amino1-3-methyl-butyric acid tert-butyl ester and (S)-{[(2S,35,45,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid tert-butyl ester (45.8 mg, 15.6 %). The mixture was treated with 2N H2504 (catalytic) in Me0H (1 mL) at 120 C for 10 min using CEM
microwave reactor to give after purification by PR-HPLC: (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-aminoI-3-methyl-butyric acid methyl ester (15.5 mg, 36.5%).
FIRMS (ES- ) 1:11/Z Calcd for C29H35C12N303+1 [(N1+11)1: 544.2128, found:
544.2127, Example 10d Preparation of (S)-2- [(2S,3 S,4S ,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyli-aminoI-3-methyl-butyric acid methyl ester Clbo CI A-M. W. 544.5 C29H35C12N303 Column separation from the above example (Example 10a) gave a mixture of (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyll-amino1-3-methyl-butyric acid tert-butyl ester and (S)-{[(2S,35,45,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid tert-butyl ester (45.8 mg, 15.6 %). The mixture was treated with 2N H2504 (catalytic) in Me0H (1 mL) at 120 C for 10 min using CEM
microwave reactor to give after purification by reverse phase chromatography (20-95% of MeCN/water): (S)-2- {[(2S,3 S,4 S,5R)-3 -(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-aminoI-3-methyl-butyric acid methyl ester (13.5 mg, 31.8%).
HRMS (ES') MIZ Calcd for C29H35C12N303+H [(11/4v1+H)l: 544.2128. found:
544.2126.
Example 11 Preparation of (S)-2- [(2R,3R,4R,5 S)-3 -(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino -3 -methyl-butyric acid =
-;
NHo 40' CI
M. W. 530.5 C28H33C12N303 A mixture of (S)-2- { [(2R,3R,4R,5 S)-3 -(3 -chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-aminoI-3-methyl-butyric acid tert-butyl ester (86.0 mg, 0.15 mmol) prepared in Example 10a and 2 N H2504 (0.5 mL) in MeCN (1 mL) was heated to 120 C for 10 min with CEM microwave reactor. The mixture was then concentrated and the residue was purified by reverse phase chromatography (20-95% of MECN/water) to give: (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyll-amino1-3-methyl-butyric acid (45.1 mg, 58.0%).
HRMS (ES' )1111Z Calcd for C28H33C12N303+H [(11/4,4+H)1: 530,1972. found:
530.1971.
Example 12 Preparation of (S)-2- [(2S,3S,4S ,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-aminoI-3 -methyl-butyric acid 01v_a N
(j14,, CI lel M. W. 530.5 C28H33C12N303 A mixture of (S)-2-1[(2S,3S,4S,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-aminoI-3-methyl-butyric acid tert-butyl ester (90 mg, 0.15 mmol) prepared in Example 10b and 2 N H2SO4 (0.5 mL) in MeCN (1 mL) was heated to 120 C for 10 min with CEM microwave reactor. The mixture was then concentrated and the residue was purified by reverse phase chromatography (20-95% of MeCN/water) to give: (S)-2-{[(2S,3S,4S,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyll-amino1-3-methyl-butyric acid (45.8 mg, 56.3%).
iIf'S (ES') nth CaIed for C28H33C12N303+1-1 [d M I 101: 530,1972, tbund:
530.1971.
Example 13 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclopropylmethyp-amide CI
CI
M. W. 514.50 C28H33C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol) prepared in Example ld, (1-aminomethyl-cyclopropy1)-methanol (30.3 mg, 0.3 mmol), HATU (76.0 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2C12 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of MeCN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclopropylmethyl)-amide (23.9 mg, 24.7 %) as a white powder.
[IRAS (ES') raiz CaJcd kir C28I-13302N302 H [(M F j: 514.2023, found:
514.2024.
Example 14 Preparation of rac-(2R,3R,4R,5S)-3-(3-Chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclobutylmethyl)-amide CI QOH
NH
µµ, CI
M. W. 528.53 C29H35C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reactd with (1-aminomethyl-cyclobuty1)-methanol (34.5 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclopropylmethyp-amide (11.2 mg, 10.6 %).
FIRMS (ES-) 111/Z Cala' for C29H35C12N302 H [(M+H)--): 528.2179, found:
528.2179, Example 15 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-tert-butyl benzylamide 01 0,1-1 So 410. NH
Cl M. W. 576.62 C34H39C12N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 4-tert-butylbenzylamine (48.98 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 4-tert-butyl-benzylamide (41.8 mg, 36.25 %).
HRMS ES)( mlz Calcd for C34H39C12N30 + H [(M+H)1: 576.2543. found:
576.2541.
Example 16 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl) pyrrolidine-2-carboxylic acid (3,3-dimethyl-buty1)-amide CI
410' NH
\`
Cl' 10 M. W. 514.54 C29H37C12N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 3,3-dimethylbutylamine (30.36 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) 15 at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl) pyrrolidine-2-carboxylic acid (3,3-dimethyl-buty1)-amide (30.4 mg, 29.5 %).
FIRMS (ES-') mi./ Cala r C29H37C12N30 H [(M-1-1-01: 514,2387. found: 514.2384.
20 Example 17 Preparation of rac-(2R,3R,4R,5 S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2,2-dimethyl-propy1)-amide CI H
40 \\
0, M. W. 500.52 C281135C12N30 25 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 2,2-dimethyl-propylamine (34.2 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2,2-dimethyl-propy1)-amide (24.6 mg, 24.6 %).
HRMS (ES-) nilz Caled for C28H35C12N30 + H [(11/4,1+H)1: 500.2230. found:
500.2229.
Example 18 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide H F
CI
= NH F
CI
M. W. 512.41 C25H26C12F3N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld, 2,2,2-trifluoroethylamine (29.7 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2C12 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was concentrated then purified by flash column (Si02, 1-20% of Et0Ac in Heptane) to afford rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (2,2-dimethyl-propy1)-amide (48.1 mg, 46.9 %).
HIS (ES-) mlz Caled for C25H26C12F3N30+ H [( M+H)1: 512.1478, found: 512.1478.
Example 19a Preparation of (2R,3S,45,5S)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-5-((S)-2-hydroxymethyl-pyrrolidine-1-carbony1)-pyrrolidine-3-carbonitrile CI
= NCR__ NH OH
Cl \\N
M. W. 514.494 C28H33C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with (S)-1-pyrrolidin-2-yl-methanol (30.3 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight. The mixture was then diluted with CH2C12 and washed with water, brine.
The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (30-95% of MeCN/water) to give (2R,3S,4S,5S)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-5-((S)-2-hydroxymethyl-pyrrolidine-1-carbony1)-pyrrolidine-3-carbonitrile (12.0 mg, 11.7 %).
FIRMS (ES-) rwrz Cala' for C28H33C12N302 H [(+H)-]: 514.2023, found: 514.2023.
Example 19b Preparation of (2S,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-54S)-2-hydroxymethyl-pyrrolidine-1-carbonyl) pyrrolidine-3-carbonitrile CI
Ow.
c i M. W. 514.494 C281-133C12N302 Reverse phase chromatography separation from the above example (Example 19a) gave (2S,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-5-((S)-2-hydroxymethyl-pyrrolidine-1-carbonyl) pyrrolidine-3-carbonitrile (18.1 mg, 17.6 %).
HRIVIS (ES-) 1:11/Z Calcd for C28H33C12N302 4- H [(M+H)-]: 514.2023, fund:
514.2023.
Example 20 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [2-(3,4-dimethoxy-pheny1)-ethyTmethyl-amide CI co,N 0 Cl Or' M. W. 608.606 C34H39C12N303 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol) prepared in Example ld was reacted with [2-(3,4-dimethoxy-pheny1)-ethyl]-methyl-amine (58.6 mg, 0.3 mmol), HATU (76.0 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [2-(3,4-dimethoxy-pheny1)-ethy1]-methyl-amide (57.3 mg, 48.26 %) as a white powder.
HRMS (ES-) miz Catod fir C34H39C12N303 H [(M+H)-I: 608.2441, found: 608.2437, Example 21 Preparation of rac-(2R,3R,4R,5 S)-3 -(3 -chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 2-(3,4-dimethoxy-phenyl)ethyl amide Cl N 0 44* NH 0 CI
M. W. 594.579 C33H37C12N303 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 2-(3,4-dimethoxy-phenyl)ethyl amine (30.3 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) to at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 2-(3,4-dimethoxy-phenyl)ethyl amide (53.6 mg, 45.07 %).
RMS (ES') raiz Calcd for C33H37C12N303 H 504.2285, found: 594.2283.
Example 22 Preparation of rac-(2R,3R,4R,5 S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide N CI
CI
=
NH
CI
M. W. 572.936 C30H29C13FN30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 3-chloro-2-fluoro-benzyl amine (47.9 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide (24.5 mg, 21.4 %).
HRMS (ES') MIZ Calcd for C301-129C13FN30 + 1-1 i(M+H)1: 572.1433. found:
572.1431.
Example 23a Preparation of (2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-1-hydroxymethy1-3-methyl-buty1)-amide CI
=NH
Oro' Cl M. W. 530.54 C29H37C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld, (R)-2-amino-4-methyl-pentan-1-ol (35.16 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2C12 and washed with water, brine.
The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (30-95% of MeCN/water) to give (2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-5 pyrrolidine-2-carboxylic acid ((R)-1-hydroxymethy1-3-methyl-buty1)-amide (26.2 mg, 24.7%).
HRMS (ES') 1111Z Calcd for C29H37C12N302 -4- 1-1 RM+1-1)'1: 530.2336, fbuncl:
530.2333.
Example 23b Preparation of (2S,3S,4S,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-10 propy1)-pyrrolidine-2-carboxylic acid ((R)-1-hydroxymethy1-3-methyl-buty1)-amide CI =
NH
CI \\N
M. W. 530.54 C29H37C12N302 Reverse phase chromatography separation from the above example (Example 23a) gave (2S,3S,4S,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-15 pyrrolidine-2-carboxylic acid ((R)-1-hydroxymethy1-3-methyl-buty1)-amide (23.3 mg, 21.9 %).
HRMS ES')( Calcd for C29H37C12N302 H [INI+H) 1: 530.2336. found:
530.2336.
Example 24 Preparation of rac-(2R,3R,4R,5 S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-20 dimethylpropy1)-pyrrolidine-2-carboxylic acid 3,4-difluoro-benzylamide Cl N
F
NH
Cl M. W. 556.49 C30H29C12F2N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 3, 4-difluoro-benzyl amine (42.94 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 3,4-difluoro-benzyl amide (53.5 mg, 48.1 %).
HRMS (ES') 1111Z Calcd for C30H29C12F2N30+ H [(I'4+H) I: 556.1729. found:
556.1728.
Example 25a Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Cl OH
= NH F OH
"
CI
M. W. 431.37 C23H24C12N202 .C2HF302 To a solution of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example lc (2 g, 4.12 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (10 mL).
The reaction mixture was stirred at room temperature for 18 h, and concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried under reduced pressure to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.1 g, 94%) HRMS (ES' ) III/Z Calcd for C23H24C12N202+ H [(M+14)1: 431.1288, found:
431.1287.
Example 25b Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide OH
CI
= NH
µ'µ
C1' N
M. W. 488.46 C26H31C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 25a (0.5 g, 1.1 mmol) was reacted with 3-amino-1-propanol (Aldrich) (0.4 g, 5.3 mmol), HATU (0.5 g, 1.31 mmol) and iPr2NEt (1 g, 7.7 mmol) in CH2C12 (30 mL) at room temperature for 24 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide as a white solid (0.56 g, 93%).
FIRMS (IS) m/z C.'aled for C26H31 Cl2N302 Fi [( M 11)1: 488.1866, than&
488.1864.
Example 26a Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile CI
F
N
CI
M. W. 292.14 C15H8C12FN
In a manner similar to the method described in Example lb, 4-chlorobenzyl cyanide (8.9 g, 59 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (Oakwood) (10 g, 63 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (300 mL) at 40 C for 5 h to give (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile as a white powder (16 g, 92%).
Example 26b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester c F
NH
1101 µ
CI
M. W. 505.46 C27H31C12FN202 In a manner similar to the method described in Example lc, [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile (2.3 g, 7.9 mmol) prepared in Example 26a, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in 1,2-dichloroethane (130 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2.7 g, 68%).
Example 26c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
NH
1101 uµ' CI
M. W. 449.36 C23H23C12FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 26b (0.8 g, 1.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.9 g, 100%).
FIRMS (ES-) rah Calcd for C23H23C12FN202+ H [(M-1-1-1)]: 449.1194. found:
449.1 194.
Example 26d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [2-(cis-2,6-dimethyl-morpholin-4-y1)-ethyl]-amide CI F
NH
M. W. 589.58 C31H39C12FN402 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.20 g, 0.36 mmol) was reacted with 4-(2-aminoethyl)-cis-2,6-dimethylmorpholine (Oakwood) (0.20 g, 1.2 mmol), HATU (0.3 g, 0.78 mmol) and iPr2NEt (0.60 g, 4.6 mmol) in CH2C12 (20 mL) at room temperature for 20 hrs to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [2-(cis-2,6-dimethyl-morpholin-4-y1)-ethyl]-amide as a white solid (0.20 g, 94%). HMS (ES') rniz Cale(' tbr C311-13902FN402¨ H [(M-41) ]: 589.2507, found: 589.2507, Example 27 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-cyclopropyl-ethyl)-amide H
CI
= NH
CI 1=1"' \\N
M. W. 498.50 C28H33C12N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 25a (0.16 g, 0.37 mmol) was reacted with 2-cyclopropylethylamine (Bridge Organics) (0.1 g, 1.1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2 mmol) in CH2C12 (20 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-cyclopropyl-ethyl)-amide as a white solid (0.11 g, 37%).
FIRMS (ES ') rn/z Cala for C28H33C12N30-i- H Mi IT) 'I: 498,2074, -found:
498.2075.
Example 28 Preparation of rac-(3- {[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino}-propy1)-carbamic acid tert-butyl ester H
CI 0.1,N
= NH
CI
M. W. 587.59 C311-140C12N402 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid prepared in Example 25a (1 g, 1.8 mmol) was reacted ',vith N-Boc-1,3-diaminopropane (Aldrich) (0.7 g, 4 mmol), HATU (1.4 g, 3.7 mmol) and iPr2NEt (2.8 g, 21 mmol) in CH2C12 (100 mL) at room temperature for 60 h to give rac-(3- {[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrro lidine-2-carbonyl] -amino } -propy1)-carbamic acid tert-butyl ester as a white solid (0.92 g, 87%).
R MS (ES )M' led for C311-140C12N402 H [(NI F I) j: 587.2550, 587.2551.
Example 29 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-amino-propy1)-amide NH
CI
= NH
CI
5 M. W. 487.47 C26H32C12N40 To a solution of rac-(3-{[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester prepared in Example 28 (0.9 g, 1.5 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 h, and concentrated. The 10 residue was then neutralized with saturated aqueous NaHCO3 solution, and then extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, concentrated, dried under reduced pressure to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-amino-propy1)-amide as a white solid (0.8 g, 100%) 15 FIRMS (ES) mjz Caled ibr C26H32C12N40 H [( M 11)1: 487.2026. found:
487.2027.
Example 30 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [3-(1-acetyl-piperidin-4-ylamino)-propyl]-amide CI H ,iNsCN_O
= NH
AO' Cl M. W. 640.65 C34H43C12N503 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propy1)-amide prepared in Example 29 (0.18 g, 0.37 mmol) was reacted with 1-acetylpiperidine-4-carboxylic acid (Lancaster) (0.7 g, 0.58 mmol), HATU (0.3 g, 0.78 mmol) and iPr2NEt (0.5 g, 3.9 mmol) in CH2C12 (20 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1-acetyl-piperidin-4-ylamino)-propyll-amide as a white solid (0.16g, 67%).
FIRMS (ES-) rntz Calcd for C34H43C12N5034- H [(M+H)-]: 640.2816, found:
640.2818.
Example 31a Preparation of intermediate [3-Methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester 00y M. W. 199.16 C11H21NO2 In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with isovatera Welly& (Alfa) (0.43 g, 5 nunoi) in CH2C12 at room temperature for 18 h to give [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.98 g, 98%).
Example 31b Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester = Ncl H
40 \\
M. W. 473.45 C26H3002N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 31a (2 g, 10 mmol) was reacted with (Z)-3-(3-chloro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile (2 g, 7.3 mmol) prepared in Example lb, AgF
(1.3 g, 10 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.7 g, 20%).
Example 31c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI
= NH
F.)EÇOH
Cl .1"µµ µN
M. W. 417.34 C22H22C12N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 31b (0.4 g, 0.85 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.4 g, 89%).
HRMS (ES') miz Caled fbr C22H22C12N202-i- H 101+H11: 417.1 1131, found: 417.1 131.
Example 31c1 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide H OH
Cl Csb NH*':C.C.4.)-1' ""
M. W. 474.43 C25H29C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 31c (0.6 g, 1.1 mmol) was reacted with 3-amino-1-propanol (Aldrich) (0.4 g, 5.3 mmol), HATU and iPr2NEt in CH2C12 at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide as a white solid (0.21 g, 40%).
HR MS (ES') Mk Ca icd for C25H29C12N302 t 1111 (II)]: 474. 1'710, found :
474,1 710.
Example 32a Preparation of intermediate {[1-(3-Chloro-pheny1)-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester IN
CI
M. W. 253.73 C13H16CN02 In a manner similar to the method described in Example la, glycine tert-butyl ester (1.31 g, 10 mmol) was reacted with 3-chlorobenzaldehyde (Aldrich) (1.4 g, 10 nwhol) in CH2C12 at room temperature for 18 h to give {[1-(3-chloro-phenyl)-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester as a plae yellow oil (2.4 g, 95%).
Example 32b Preparation of intermediate (Z)-2-(4-chloro-phenyl)-5,5-dimethyl-hex-2-enenitrile 1.1 M. W. 233.74 C14H16C1N
In a manner similar to the method described in Example lb, 4-chlorobenzyl cyanide (4.5 g, 30 mmol) was reacted with 3,3-dimethyl-butyraldehyde (Aldrich) (3 g, 30 mmol), methanolic solution (25 wt%)of sodium methoxide (7 mL, 30 mmol) in methanol (130 mL) at room temperature for 3 h to give (Z)-2-(4-chloro-phenyl)-5,5-dimethyl-hex-2-enenitrile as a colorless oil (5 g, 71%).
Example 32c Preparation of intermediate rac-(2R,3R,4R,5S)-5-(3-Chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-3-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester OfC)?( NH
C
CI I
M. W. 487.47 C27H32C12N202 In a manner similar to the method described in Example lc, {[1-(3-chloro-pheny1)-meth-(E)-ylidene]-aminol-acetic acid tert-butyl ester prepared in Example 32a (2.6 g, 11 mmol) was reacted with (Z)-2-(4-chloro-phenyl)-5,5-dimethyl-hex-2-enenitrile (2 g, 7.9 mmol) prepared in Example 32b, AgF (1.3 g, 10 mmol), and triethylamine (2.2 g, 22 mmol) in 1,2-dichloroethane (100 mL) at room temperature for 24 h to give rac-(2R,3R,4R,5S)-5-(3-Chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-3-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 31%).
HRMS (ES') rulz Cato(' for C27H32C12N202-'- H1(I4+11)' I: 487.1914, found:
487.1912.
Example 32d Preparation of intermediate rac-(2R,3R,4R,5S)-5-(3-Chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-3-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid of0H
NH
10' 110 c, FOH
F¨Ao CI
M. W. 431.37 C23H24C12N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-5-(3-Chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 32c (1.2 g, 2.5 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-5-(3-Chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyfl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (1.0 g, 76%).
HIRS (ES ) miz Ca la! for C23H24C12N202+ i1 [(N1-HI-1) ]: 431.1288, found: 431 1288.
Example 32e Preparation of rac-(2R,3R,4R,5R)-5-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-3-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide OH
CI
CI N
M. W. 488.46 C26H31C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5R)-5-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 32d (0.6 g, 1.1 mmol) was reacted with 3-amino-1-propanol (Aldrich) (0.6 g, 8 mmol), HATU and iPr2NEt in CH2C12 at room temperature to give rac-(2R,3R,4R,5R)-5-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide as a yellow solid (0.12 g, 22%).
HRMS (ES') III/Z Calcd for C26H31 Cl2N3 02-1- H [(M+H) I: 488.1866, found:
488.1864.
Example 33a Preparation of intermediate (S)-2-[3,3-Dimethyl-but-(E)-ylideneamino]-propionic acid tert-butyl ester AN
\/*<
5 M. W. 227.35 C13H25NO2 A mixture of L-alanine tert-butyl ester hydrochloride (Bachem) (1.8 g, 10 mmol) and MgSO4 in CH2C12 (100 mL) was added triethylamine (1.5 g, 15 mmol). The mixture was stirred at room temperature for 1 h, and 3,3-dimethyl-butyraldehyde (1 g, 10 mmol) was added.
The reaction mixture was stirred at room temperature for 18 h. The mixture was filtered, and the filtrate was 10 washed with water, brine, and concentrated. The residue was dried under reduced pressure to give (S)-2-[3,3-dimethyl-but-(E)-ylideneamino]-propionic acid tert-butyl ester as colorless oil (2,3 g, 100%) which was used without further purification.
Example 33b 15 Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-Chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-2-methyl-pyrrolidine-2-carboxylic acid tert-butyl ester CI (:).0?( 0, M. W. 501.50 C28H34C12N202 In a manner similar to the method described in Example lc, (S)-2-[3,3-dimethyl-but-(E)-20 ylideneamino]-propionic acid tert-butyl ester prepared in Example 33a (2.4 g, 11 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (2.4 g, 8.8 mmol) prepared in Example lb, AgF (1.6 g, 13 mmol), and triethylamine (2.4 g, 24 mmol) in 1,2-dichloroethane (150 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-Chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic 25 acid tert-butyl ester as a white foam (2.4 g, 54%).
FIRMS (ES') mlz Cala for C28H34C121\1202-1- 11 [1M 50i .2070, found:
501.2066.
Example 33c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-2-methyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid cl of0H
= NH FLOH
CI NµN
M. W. 445.39 C24H26a2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 33b (1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-2-methyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.1 g, 98%).
R. MS (ES') ni/z. Coiled for C24H26C12N202 1 1 [(M-F1-1)']: 445.1444, found:
445.1443.
Example 33d Preparation of rac-(2R,3R,4R,5 S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-2-methyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide OH
CI
= NH
N.\
CID"' M. W. 502.48 C27H33C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,55)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 33c (0.4 g, 0.7 mmol) was reacted with 3-amino-1-propanol (Aldrich) (0.4 g, 5.3 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (1 g, 7.7 mmol) in CH2C12 (30 mL) at room temperature for 24 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-2-methyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide as a white solid (0.21 g, 60%).
HRMS (ES') 1:111Z Calcd for C27H33C12N302-4- 1-1 [(,14-1-1)'1: 502.2023, found: 502.2021.
Example 34a Preparation of intermediate [2-Cyclopentyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester OO
IUD
M. W. 225.33 C13H23NO2 In a manner similar to the method described in Example la, glycine tert-butyl ester (0.7 g, 5 mmol) was reacted with 2-cyclopentylacetaidehyde Bctaphartna) (0.9 g. 8 mmol) in CH2C12 at room temperature for 20 h to give [2-cyclopentyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1 g, 90%).
Example 34b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid tert-butyl ester CI F
= 1\1111-1 0,...
CI
M. W. 517.48 C281-I31C12FN202 In a manner similar to the method described in Example lc, [2-cyclopentyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 34a (1 g, 4.4 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile (0.9 g, 3 mmol) prepared in Example 26a, AgF (1.3 g, 10 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (150 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid tert-butyl ester as a white foam (0.4 g, 26%).
Example 34c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid trifluoroacetic acid CI F orOH
= NH F OH
10 ' \'µ
Cl M. W. 461.37 C24H23C12FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid tert-butyl ester prepared in Example 34b (0.4 g, 0.77 mmol) was reacted ,vvith trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid trifluoroacetic acid as a off white solid (0.5 g, 100%).
Example 34d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide NH OH
I.1"" =
CI
M. W. 548.48 C281-13202FN303 In a manner similar to the method described in Example 3b, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid trifluoroacetic acid prepared in Example 34c (0.4 g, 0.71 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.2 g, 1.4 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (0.6 g, 4.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.14 g, 36%).
FIRMS (ES') rd/z Ca for C28H32C12FN303 H [( WI: 548,1878, found:
548.1880.
Example 35 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide CI F 0(1\5<" OH
= NH
CI
M. W. 520.47 C27H32C12FN302 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.2 g, 0.36 mmol) was reacted with 2-amino-2-methyl-1-propanol (Fluka) (0.2 g, 2.2mmol), HATU (0.3 g, 0.78 mmol) and iPr2NEt (0.5 g, 3.8 mmol) in CH2C12 (10 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide as a white solid (0.17 g, 91%).
EIRMS (ES-) mlz Cated for C27H3202FN302+ H M+/-01: 520.1929, found: 590.1929.
Example 36 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-hydroxy-2,2-dimethyl-propy1)-amide OH
CI F
= NH
CI
M. W. 534.5 C28H34C12FN302 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.2 g, 0.36 mmol) was reacted with 3-amino-2,2-dimethyl-1-propanol (TCI-US) (0.2 g, 2 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.2 g, 1.6 mmol) in CH2C12 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-2,2-dimethyl-propy1)-amide as a white solid (0.16 g, 83%).
EIRMS (ES-) mh Ca led for C28H34C12FN302+ H [( M-1-1-01: 534.2085, found:
534.2084.
Example 37 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide OH
CI F
= NH
110ClN
""
M. W. 536.47 C27H32C12FN303 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.3 g, 0.54 mmol) was reacted with 2-(2-aminoethyl)ethanol (Aldrich) (0.15 g, 1.4 mmol), HATU (0.3 g, 0.75 mmol) and iPr2NEt (0.6 g, 5 4.8 mmol) in CH2C12 (20 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide as a white solid (0.18 g, 62%).
HRMS (ES-) miz Caled for C27H32C12FN303+ H M+FOI: 536.1878, found: 536.1877.
10 Example 38 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-acetylamino-ethyl)-amide CI F
= NH
CI .
M. W. 533.47 C27H31C12FN402 15 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.3 g, 0.54 mmol) was reacted with N-acetylethylenediamine (Aldrich) (0.15 g, 1.5 mmol), HATU (0.3 g, 0.75 mmol) and iPr2NEt (0.6 g, 4.8 mmol) in CH2C12 (20 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-20 chloro-2-fluoro-pheny1)-4-(4-chloro-pheny0-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-acetylamino-ethyl)-amide as a white solid (0.24 g, 83%).
HR JS (FS') m/z Calcd ft-if C27H3102FN402 [t M-1 1-01: 533,1881, found:
533.1882.
Example 39 25 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-imidazo1-1-yl-propy1)-amide eNN
CI F N
NH
CI
M. W. 556.51 C29H32C12FN50 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.2 g, 0.36 mmol) was reacted with 1-(3-aminopropopyl)imidazole (Aldrich) (0.15 g, 1.2 mmol), HATU (0.3 g, 0.75 mmol) and iPr2NEt (0.5 g, 3.6 mmol) in CH2C12 (20 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-imidazol-1-yl-propy1)-amide as a white solid (0.19 g, 94%).
HMIS (ES') nblz Cala C29H32C12FN50 1 11 1( M11101: 556.2041. found:
556.2040.
Example 40 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-4-hydroxy-3-methyl-buty1)-amide CI F
= NH
0%." 4%µ, CI
M. W. 534.5 C28H34C12FN302 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.16 g, 0.29 mmol) was reacted with (R)-4-amino-2-methyl-1-butanol (TCI-US) (0.1 g, 1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2 mmol) in CH2C12 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-4-hydroxy-3-methyl-butyl)-amide as a white solid (0.1 g, 65%).
HRMS (ES') mlz Caled for C28H34C12FN302+ H [(M+11)'1: 534.2085, found:
534.208.4.
Example 41 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid cyclopropylmethoxy-amide CI F
= NH
CI
M. W. 518.46 C27H30C12FN302 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.15 g, 0.27 mmol) was reacted with O-S cyclopropylmethylhydroxyamine (HUHU Tech) (0.1 g, 1.1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2 mmol) in CH2C12 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid cyclopropylmethoxy-amide as a white solid (30 mg, 21%).
IIRMS (ES') miz Cala ibt= C27H30C12FN3024- ri [(M fl]: 518.1772, found:
518.1773, Example 42a Preparation of intermediate rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester CI 0/.02( = NH
CI \\ 1101 CI
M. W. 527.88 C28H25C13N202 In a manner similar to the method described in Example lc, 41-(3-Chloro-pheny1)-meth-(E)-ylidene]-aminol-acetic acid tert-butyl ester prepared in Example 32a (2 g, 7.6 mmol) was reacted with (Z)-3-(3-chloro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile (0.55 g, 2 mmol) prepared in Example lb, AgF (1.3 g, 10 mmol), and triethylamine (1.9 g, 19 mmol) in dichloromethane (30 mL) at 50 C for 20 h to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.45 g, 44%).
HRMS (ES-) miz Calcd, for C28H25C13N202 H [(1\4+H)-1: 527.1055, found:
527.1051.
Example 42b Preparation of intermediate rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI of0H
NH
"
M. W. 471.77 C24H17C13N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 42a (0.45 g, 0.85 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.49 g, 98%).
HRMS (ES') Tri1.7. Ca led for C24H17C13N202+ H [(N1 j: 471.0429, found:
471,0429.
Example 42c Preparation of rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide NH IC+
C
CI
M. W. 598.96 C31F13003N303 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 42b (0.3 g, 0.5 mmol) was reHcted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.3 g, 2 mmol), HATU (0.3 g, 0.75 mmol) and iPr2NEt (0.6 g, 4 mmol) in CH2C12 (30 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl]-amide as a off white solid (0.25 g, 83%).
HRMS (ES +) rniz Calcd for C31F130C13N303 H [(M+H)+]: 598.1428, found:
598.1424.
Example 42d Preparation of rac-(2R,3R,4R,5 S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Cl OH
CI
NH
CI
µµ I101 M. W. 558.89 C28H26C13N303 To a solution of rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 42c (0.4 g, 0.66 mol) in tetrahydrofuran (10 mL) was added aqueous HC1 solution (1N, mL). The reaction mixture was stirred at room temperature for 2 h, then concentrated. Then the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, aqueous saturated NaHCO3, brine, dried over MgSO4, concentrated, dried 5 under reduced pressure to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyp-amide as a white solid (0.2 g, 89%).
HRMS (ES-) mlz Cated for C281-12603N303-, H [(M+H 11: 558.1113, found: 558. 11 10.
10 Example 43a Preparation of intermediate [2-ethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester oY
M. W. 213.32 C12H231\102 In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted i 2-et hylbta yra Idell2yrde (Aldrich) (0.55 g, 5 mmo11 in CH2C12 at room temperature for 18 h to give [2-ethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1 g, 94%).
Example 43b Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI orOK
NH
110"µµ \.%
CI
M. W. 487.5 C27H32C12N202 In a manner similar to the method described in Example lc, [2-ethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 43a (1 g, 4.7 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.91 g, 3.3 mmol) prepared in Example lb, AgF (1.5 g, 12 mmol), and triethylamine (1.9 g, 19 mmol) in 1,2-dichloroethane (50 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 68%).
Example 43c 5 Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid = NH FLOH
C I
M. W. 431.37 C23H24C12N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-10 phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 43b (1.1 g, 2.3 mmol) was reacted v.iiiitrifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.2 g, 98%).
15 HRMS ES)( mitz Calcd for C23H24C12N202 [(M+H) `I: 431.1288, found: 431.1286.
Example 43d Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI
NH OH
1101 P'µ
CI
M. W. 518.48 C27H33C12N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 43c (0.55 g, 1 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.2 g, 1.3 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (0.2 g, 1.5 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.5 g, 96%).
H[RMS (ES-) ralz Calcd for C27H33C12N3034- H M+1-1)1: 518.19727 found:
518.1970.
Example 44a Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide OH
NH
CI
M. W. 536.47 C27H32C12FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.25g, 0.44 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.2 g, 1.3 mmol), HATU (0.3 g, 0.79 mmol) and iPr2NEt (0.5 g, 3.9 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21g, 89%).
HR MS (ES ) Trilz Ca tcd for C27H32C12FN303 H 536,1 878, found: 536.1875.
Example 44b Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
OH"
NH
CI
M. W. 536.47 C27H32C12FN303 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.19 g) was separated by chiral SFC chromatography to provide chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (85 mg, 45%) and chiral-(2S,3R,4SR,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (81 mg, 43%).
Example 45 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
NH OH
CI
M. W. 504.46 C26H31C12N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 31c (0.4 g, 0.75 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.25 g, 1.6 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (1 g, 7.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.4 g, 95%).
HRMS (ES') MIZ Calcd for C26H31 Cl2N3 03-1- H [(M-41)' ]: 504.1815, found:
50.4.1815.
Example 46a Preparation of intermediate rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester CI ofiCy 40' \\
CI
M. W. 473.45 C26H30C12N202 In the preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester as described in Example 31b, rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester was obtained as the second product: white powder, Yield: 0.82 g, 24%.
HR1V1S (ES) Calcd for C26H30C12N202 H [0,4+H)]: 473.1757. found:
,173.1756.
Example 46b Preparation of intermediate rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI
NH F..".F.õOH
õõ
\\
CI
M. W. 417.34 C22H22C12N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 46a (0.6 g, 1.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.6 g, 89%).
Example 46c Preparation of rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
= 0 OH
NH
*kw CI
M. W. 504.46 C26H31C12N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 46b (0.6 g, 1.1 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.3 g, 2 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (1.2 g, 9.3 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HO
solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.6 g, 95%).
FIRMS (ES-) raiz Calcd for C26H31C12N303-1.- H [(1+H)1: 504.1815, found:
504.18 I 6.
Example 47a Preparation of intermediate rac-(2R,3MR,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester CI ic,(0?( NH
CI 1.1 C
M. W. 487.5 C27H3202N202 In the preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as described in Example 43b, rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester was obtained as the second product: white foam, Yield, 0.26 g, 16%.
Example 47b Preparation of intermediate rac-(2R,3R4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI of.OH
NH FOH
W
CI =c F
M. W. 431.37 C23H24C12N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 47a (0.25 g, 0.5 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.2 g, 73%).
f-1RMS (ES) T1VZ Ca la! for C23H24C12N202+ ]: 431.1288, found: 431 .1285.
Example 47c Preparation of rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI
OH
= NH
CI \\N
r 5 M. W. 518.48 C27H33C12N303 In a manner similar to the method described in Example 42e, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 47b (0.27 g, 0.5 mmol) was routed with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.2 g, 1.3 mmol), HATU (0.4 g, 1.1 mmol) and 10 iPr2NEt (0.4 g, 3 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.23 g, 88%).
FIRMS (ES ') ITI/Zlod for C27H33C12N303+ H kM+H)1: 518.19725 found: 518.1971.
Example 48a Preparation of intermediate (1-ethyl-propylideneamino)-acetic acid tert-butyl ester M. W. 199.16 C111-121NO2 A mixture of glycine tert-butyl ester (Alfa) (0.66 g, 10 mmol) and 3-pentanone (6 g, 70 mmol) in ethanol (6 mL) was heated at 110 C in a sealed tube for 48 h. The reaction mixture was concentrated and dried in vacu to give crude (1-ethyl-propylideneamino)-acetic acid tert-butyl ester as a colorless oil (1.0 g). The crude product contains unreacted glycine tert-butyl ester and was used without further purification.
Example 48b Preparation of intermediate rac-(2R,3MR)-3-(3-chloro-pheny1)-4-(4-ehloro-pheny1)-4-eyano-5,5-diethyl-pyrrolidine-2-carboxylic acid tert-butyl ester CI
NH
CI
M. W. 473.45 C26H30a2N202 In a manner similar to the method described in Example lc, crude (1-ethyl-propylideneamino)-acetic acid tert-butyl ester prepared in Example 48a (1.2 g, 6 mmol) was roacted with (Z)-3-(3-chloro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile (0.7 g, 2.5 mmol) prepared in Example lb, AgF (1.9 g, 15 mmol), and triethylamine (2.5 g, 25 mmol) in 1,2-dichloroethane (130 mL) at room temperature for 10 h to give rac-(2R,3R,4R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-eyano-5,5-diethyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a yellow gum (0.33 g, 28%).
Example 48c Preparation of intermediate rac-(2R,3R4R)-3-(3-chloro-pheny1)-4-(4-ehloro-pheny1)-4-eyano-5,5-diethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI
= NH
FÇOH
CI 11 11"µ \\I\I
M. W. 417.34 C22H22C12N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 48c (0.33 g, 0.7 mmol) was reacted \ivith trifluoroacetie acid in dichloromethane at room temperature to give rac-(2R,3R,4R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid trifluoroacetie acid as a off white foam (0.35 g, 96%).
FIRMS (ES-) mlz Caied for C22H22C12N202+ H )-I: 417.1 13 1.0429, found:
417,1132.
Example 48d Preparation of rac-(2R,3R,4R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Cl OH
= NH
µ
CI
M. W. 504.46 C26H31C12N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 48c (0.33 g, 0.62 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1 mmol), HATU (0.34 g, 0.89 mmol) and iPr2NEt (1 g, 7.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a off white solid (0.4 g, 95%).
FIRMS (ES') m/z Calcd for C26H31 Cl2N303 H [(MHI)']: 504.1815, found:
50,1.1815.
Example 49a Preparation of intermediate [2-methyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester 0:200y-M. W. 185.27 C10H19NO2 In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with isobutyraldehyde (Aldrich) (OA g, 5 rnmol) in CH2C12 at room temperature for 20 h to give [2-methyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.9 g, 97%).
Example 49b Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid tert-butyl ester CI
NH
101"' CI
M. W. 459.42 C25H28C12N202 In a manner similar to the method described in Example lc, [2-methyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 49a (1 g, 5.4 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.85 g, 3.1 mmol) prepared in Example lb, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.64 g, 45%).
Example 49c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI c;,e0H
= NH
F..EÇOH
[110 .%µ
CI
M. W. 403.31 C21ii20C12N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 49b (0.64 g, 1.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.7 g, 100%).
FIRMS (ES) rit/z Calcd for C211420C12N202-+ H [( M IN: 403.0975, found:
403.0974.
Example 49d Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
=
NH OH
101 \'µ
CI
M. W. 490.43 C25H29C12N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 49c (0.5 g, 0.97 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.25 g, 1.7 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (1 g, 7.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.25 g, 52%).
HMIS (ES) rmiz Calcd fbr C25H29C12N303 t H [(Mi I {)]: 490.1659, found:
490.1657.
Example 50a Preparation of intermediate {[1-cyclohexyl-meth-(E)-ylidene]-aminol-acetic acid tert-butyl ester M. W. 225.33 C13H231\102 In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with cyclohexallecurbalcichyde (Aldrich) (0,6 g, 5 mmol) in CH2C12 at room temperature for 20 h to give {[1-cyclohexyl-meth-(E)-ylidene]-aminol-acetic acid tert-butyl ester as a colorless oil (1.2 g, 100%).
Example 50b Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid tert-butyl ester CI c;,C7( NH
.1" \\
M. W. 499.49 C28H3202N202 In a manner similar to the method described in Example lc, {[1-cyclohexyl-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester prepared in Example 50a (1.2 g, 5.3 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (1 g, 3.7 mmol) prepared in Example lb, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.69 g, 38%).
5 Example 50c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI
= NH
µµ
CI N =
M. W. 443.38 C24H24C12N202.C2HF302 10 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 50b (0.69 g, 1.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off 15 white solid (0.8 g, 100%).
HRMS (ES) raiz Calcd {by C24H24C12N202-t H [(M IN: 443,1288, found: 443.1286.
Example 50d Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
= NH OH
110 \µ
M. W. 530.49 C28H33C12N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 50c (0.5 g, 0.76 mmol) was reacted with 2-((S)-2,2-25 dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.3 g, 2 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (0.9 g, 7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.25 g, 62%).
FIRMS (ES-) fillz Caled for C28H33C12N3034- H kM+H)--1: 530.1972, found:
530.197 Example 51a Preparation of intermediate [2,2-dimethyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester M. W. 199.16 C11H21NO2 In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with triincillytacetaldettyde (Aldrich) (0.42 g, 5 ltitnot) in CH2C12 at room temperature for 20 h to give [2,2-dimethyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.0 g, 100%).
Example 51b Preparation of intermediate rac-(2R,3S,4R,5S)-5-tert-buty1-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester Cl F oe0?c/
CI
M. W. 491.44 C26H29C12FN202 In a manner similar to the method described in Example lc, [2,2-dimethyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 51a (1 g, 5 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile (0.8 g, 2.7 mmol) prepared in Example 26a, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (50 mL) at room temperature for 24 h to give (2R,3S,4R,5S)-5-tert-Buty1-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.4 g, 30%).
Example 51c Preparation of intermediate rac-(2R,3S,4R,5S)-5-tert-buty1-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
= N FFOH
1(!) CI [1101" \\N
M. W. 435.33 C22H21 C12FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-tert-Buty1-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 51b (0.3 g, 0.6 mmol) was reactd with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-tert-Buty1-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.4 g, 100%).
FIRMS (ES') iniz (Ailed for C22H21C12FN202-F- 1-1 [(NI -F-H)']: 435.1037, found: 435.1036, Example 51d Preparation of rac-(2R,3S,4R,5S)-5-tert-buty1-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F OH
OH
= NH
NN, CI
M. W. 522.45 C26H30C12FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 51c (0.4 g, 0.73 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.2 g, 1.3 mmol), HATU (0.3 g, 0.79 mmol) and iPr2NEt (0.6 g, 4.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-tert-buty1-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.22 g, 58%).
FIRMS (ES ni/z Calcd for C26H30C12FN303 l [(NI 1 l 22.1721; found:
522.1719, Example 52a Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile CI
F
CI
M. W. 310.13 C15H7C12F2N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (5 g, 30 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5 g, 32 mmol), methanolic solution (25 wt%) of sodium methoxide (21 mL, 92 mmol) in methanol (200 mL) at 45 C for 5 h to give (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile as a white powder (9 g, 97%).
Example 52b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F c,(0?(' NH
Cl F N
M. W. 523.46 C27H30C12 F2N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.3 g, 11 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (2.5g, 8 mmol) prepared in Example 52a, AgF (0.7 g, 5.5 mmol), and triethylamine (2.9 g, 29 mmol) in dichloromethane (200 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (3 g, 64%).
Example 52c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F of0H
= NH
CI FN
M. W. 467.35 C23H2202P2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 52b (0.4 g, 0.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.5 g, 100%).
FIRMS (ES) rniz Caled for C23H22C12F2N202+ j: 467.1099, fbund: 467.1098.
Example 52d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
AO'NH OH
=N\
CI
M. W. 554.46 C27H31C12F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.4 g, 0.69 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.25 g, 1.7 mmo1), HATU
(0.35 g, 0.92 mmol) and iPr2NEt (0.75 g, 5.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.26 g, 84%).
HRMS (ES-) mlz Cated for C27H31 Cl2F2N303-,- H[( M+14)]: 554.1784, found:
554.1783.
Example 52e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F n *NH OH
Cl 5 M. W. 554.46 C27I-131C12F2N303 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.3g) was separated by chiral SFC chromatography to provide chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-10 pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (120 mg, 40%) and chiral-(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (121 mg, 40%).
15 Example 53a Preparation of intermediate rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F0 Ox, \\
CI F N
M. W. 523.46 C27H30C12F2N202 20 In preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as described in Example 52b, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester was obtained as the second product: a white foam (0.98 g, 21%).
Example 53b Preparation of intermediate rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Cl F0 OH
'410' NH
F. 11 AO
CI F -M. W. 467.35 C23H2202P2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2S,3S,4R,SS)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 53a (0.4 g, 0.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3S,4R,5S)-3-(3-Chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.5 g, 100%).
FIRMS (ES) miz Caled for C23H22C12F2N202+i1RNI-F I-1) j: 467.1099, fbund:
467.1099, Example 53c Preparation of rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide OH
NH
CI
M. W. 554.46 C27H31C12F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2S,3S,4R,5S)-3-(3-Chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 53b (0.3 g, 0.5 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1 mmol), HATU
(0.3 g, 0.79 mmol) and iPr2NEt (0.4 g, 3.1 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.26 g, 94%).
HIS (ES-) mlz Calcd for C27H31 Cl2F2N303-,- H[( M+14)]: 554,1784, found:
554.1782.
Example 54a Preparation of intermediate (Z)-2-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-pheny1)-acrylonitrile CI
F
Br M. W. 336.59 C151-1813rC1FN
In a manner similar to the method described in Example lb, 4-bromophenylacetonitrile (Aldrich) (4.5 g, 23 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5.2 g, 33 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (150 mL) at 50 C for 3 h to give (Z)-2-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-acrylonitrile as a white powder (7.8 g, 100%).
Example 54b Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-bromo-pheny1)-3-(3-ehloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F O
=NH
B
r M. W. 549.92 C27H31BrCIFN202 In a manner similar to the method described in Example lc, [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (1.1 g, 5 mmol) was reactod with (Z)-2-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-pheny1)-acrylonitrile (1.2 g, 3.6 mmol) prepared in Example 54a, AgF (1.3 g, 10 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 3 h to give rae-(2R,3S,4R,5S)-4-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 56%).
Example 54c Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F of0H
NH F-./....õOH
"
Br *IP \\NI
M. W. 493.81 C23H23BrC1FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-4-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 54b (1.1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (1.2 g, 99%).
FIRMS (ES-) ryitz Calcd for C23H23BrC1FN202¨ H Riv4-i+1)1: 493.0688; found:
493.0689.
Example 54d Preparation of rac-(2R,3S,4R,5S)-4-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide OH
NH
Br M. W. 580.92 C27H32BrC1FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,35,4R,55)-4-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 54c (0.3 g, 0.49 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1 mmol), HATU
(0.23 g, 0.6 mmol) and iPr2NEt (0.4 g, 3.1 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-4-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.18 g, 63%).
IIR NIS (ES ) /1117. Ca tat for C27H32BrC1FN303-- H [(M-1- FM: 580.1373, found: 580.1372 Example 55a Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-fluoro-pheny1)-acrylonitrile CI
F.
M. W. 275.69 C15I-I8C1F2N
In a manner similar to the method described in Example lb, 4-fluorophenylacetonitrile (Aldrich) (3.5 g, 26 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5.3 g, 34 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (200 mL) at 50 C for 3 h to give (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-fluoro-pheny1)-acrylonitrile as a white powder (5.7 g, 80%).
Example 55b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-4-(4-fluoro-pheny1)-pyrrolidine-2-carboxylic acid tert-butyl ester Ci F 0.07( 1101""
M. W. 489.01 C27H31C1F2N202 In a manner similar to the method described in Example lc, [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (1.1 g, 5 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-fluoro-pheny1)-acrylonitrile (1.25 g, 4.5 mmol) prepared in Example 55a, AgF (1.6 g, 13 mmol), and triethylamine (1.6 g, 16 mmol) in dichloromethane (100 mL) at room temperature for 5 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.6 g, 72%).
Example 55c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-4-(4-fluoro-pheny1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
"'µ FtÇOH
oi0H
41' NH
w \'µ
5 M. W. 432.90 C23H23C1F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 55b (1.6 g, 3.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-10 phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.7 g, 94%).
Example 55d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5 -(2,2-dimethyl-15 propy1)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH OH
M. W. 520.02 C27H32C1F2N303 In a manner similar to the method described in Example 42e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic 20 acid trifluoroacetic acid prepared in Example 55c (0.4 g, 0.73 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.2 g, 1.4 mmol), HATU (0.3 g, 0.8 mmol) and iPr2NEt (0.6 g, 4.6 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-4-(4-fluoro-phenyl)-pyrrolidine-2-25 carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 55%).
FIRMS (ES ') rn/z Cated for C27H32C1F2N303-t- H [(M+H ) ]: 520.2173. found:
520.2 I 75.
Example 56a Preparation of intermediate (Z)-3-(3-Chloro-2-fluoro-pheny1)-2-(2,4-dichloro-pheny1)-acrylonitrile CI
F
CI
CI
M. W. 326.59 C15H7C13FN
In a manner similar to the method described in Example lb, 2, 4-dichlorobenzyl cyanide (6 g, 32 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (6 g, 38 mmol), methanolic solution (25 wt%) of sodium methoxide (30 mL, 131 mmol) in methanol (200 mL) at 50 C
for 3 h to give (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(2,4-dichloro-pheny1)-acrylonitrile as a white powder (7 g, 67%).
Example 56b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F c3,(0.-2( = NI tH
IS
CI CI N
M. W. 539.91 C27H30C13FN202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(2,4-dichloro-pheny1)-acrylonitrile (2.2 g, 6.7 mmol) prepared in Example 56a, AgF (2 g, 16 mmol), and triethylamine (5 g, 50 mmol) in dichloromethane (200 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2.4 g, 66%).
Example 56c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F (DeOH
= NH FOH
CI OIN
M. W. 483.80 C23H22C13FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 56b (2.4 g, 7.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.7 g, 100%).
Example 56d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
=
NH OH
CI CI
M. W. 570.92 C27H3103FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 56c (0.6 g, 1 mmol) was reacted with 24(S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.3 g, 2 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (0.9 g, 7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.5 g, 88%).
FIRMS (ES ') iablz Calcd tbr C27H31C13FN303 Fi 1(M -FM' -1: 570.1488, round:
570.107, Example 56e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH OH
CI *PC' I \µI\I
M. W. 570.92 C27H31C13FN303 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.5 g) was separated by chiral SFC chromatography to provide chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (200 mg, 40%) and chiral-(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (220 mg, 44%).
Example 57a Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-methyl-pheny1)-acrylonitrile CI
F
CI N
M. W. 306.17 C16H10C12FN
Step A.
A mixture of 4-chloro-2-methylbenzyl alcohol (Aldrich) (5 g, 32 mmol) in thionyl chloride (20 mL) was heated at refluxing (100 C) for 30 min. The mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous NaHCO3 solution, water, brine, dried over MgSO4, and concentrated to give 4-chloro-2-methylbenzyl chloride as a light yellow oil (5.2 g, 93%).
Step B.
To a solution of 4-chloro-2-methylbenzyl chloride (5.2 g, 30 mmol) in ethanol (40 mL) was added an aqueous solution (30 mL) of KCN (5 g, 77 mmol) at room temperature.
The reaction mixture was then heated at 100 C for 2 h. The mixture was cooled to room temperarure and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;10, then 1:4) to give 4-chloro-2-methylbenzyl cyanide as a yellow oil (3.5 g, 66%).
Step C
In a manner similar to the method described in Example lb, 4-chloro-2-methylbenzyl cyanide (3.5 g, 21 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5 g, 32 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (100 mL) at 50 C for 5 h to give (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-methyl-pheny1)-aerylonitrile as a white powder (4 g, 62%).
Example 57h Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny0-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F c3,(0.-2( = NI tH
CI 1101 \\N
M. W. 519.49 C28H33C12FN202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-methyl-pheny1)-acrylonitrile (2.3 g, 7.5 mmol) prepared in Example 57a, AgF (1.3 g, 10 mmol), and triethylamine (2.8 g, 28 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.9 g, 49%).
Example 57c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
= NH FJOH
"
CI
M. W. 463.38 C24H25C12FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 57b (1.9 g, 3.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.1 g, 98%).
Example 57d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI FOH
OH
= NH
oro CI
M. W. 550.50 C281134C12FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 57c (0.4 g, 0.69 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.2 g, 1.4 mmol), HATU
(0.4 g, 1.1 mmol) and iPr2NEt (0.8 g, 6.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.29 g, 76%).
HRMS ES)( Calcd for C28H34C12FN303+ H [0,1+11)' I: 550.2034, found:
550.2036, Example 58a Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-methoxy-pheny1)-acrylonitrile CI
CI
M. W. 322.17 C16H10C12FN0 Step A.
In a manner similar to the method described in Example 57 Step A, 4-chloro-2-methoxybenzyl alcohol (Aldrich) (4.9 g, 28 mmol) was reacted with thionyl chloride (20 mL) to give 4-chloro-2-methoxybenzyl chloride as a white solid (5.1 g, 95%).
Step B
In a manner similar to the method described in Example 57 Step B, 4-chloro-2-methoxybenzyl chloride (5.1 g, 27 mmol) was reacted with NaCN (3 g, 61 mmol) in ethanol (40 mL) and water (20 mL) at 100 C for 8 h to give 4-chloro-2-methoxybenzyl cyanide as a colorless oil (1.8 g, 36%) Step C
In a manner similar to the method described in Example lb, 4-chloro-2-methoxybenzyl cyanide (1.8 g, 10 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (2 g, 13 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (50 mL) at 50 C for 2 h to give (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-methoxy-pheny1)-acrylonitrile as a white powder (2.1 g, 65%).
Example 58b Preparation of intermediate rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester Cl F o OK
410. NH
1101 µµ
M. W. 535.49 C28}133C12FN203 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was roacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-methoxy-pheny1)-acrylonitrile (1.8 g, 5.6 mmol) prepared in Example 58a, AgF (1.7 g, 13 mmol), and triethylamine (2.8 g, 28 mmol) in dichloromethane (100 mL) at room temperature for 24 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methoxy-pheny1)-4-cyano-5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.8 g, 60%).
Example 58c 1 0 Preparation of intermediate rac-(2S,3S,4R,5 S)-3 -(3 -chloro -2-fluoro-pheny1)-4-(4-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid = NH
11000 N w CI
M. W. 479.38 C24H25C12FN203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluor -pheny1)-4-(4-chloro-2-metho xy-p heny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carboxylic acid tert-butyl ester prepared in Example 58b (1.3 g, 2.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.5 g, 100%).
Example 58d Preparation of rac-(2S,3S,4R,5 S)-3-(3 -chloro-2-fluoro-pheny1)-4-(4-chloro -2-methoxy-p heny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F o OH
= NH
M. W. 566.50 C28H34C12FN304 In a manner similar to the method described in Examples 42c, 42d, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 58c (0.4 g, 0.67 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.25 g, 1.7 mmol), HATU
(0.4 g, 1.1 mmol) and iPr2NEt (0.6 g, 4.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.23 g, 61%).
FIRMS (ES-) rwrz Cala' for C28H34C12FN304+ H [(M+H )]: 566.1983. found:
566.1983.
Example 59a Preparation of intermediate [2-cyclohexyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester M. W. 239.36 C14H25NO2 In a manner similar to the method described in Example la, glycine tert-butyl ester (1.3 g, 10 mmol) was reacted with 2-c7yrclohexylacetaldebyde (Beiapharma) (1.3 g, 1) nimol) in CH2C12 at room temperature for 5 h to give [2-cyclohexyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.3 g, 96%).
Example 59b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester CI F n = r: NH
CI
M. W. 531.50 C29H33C12FN202 In a manner similar to the method described in Example lc, [2-cyclohexyl-eth-(E)-ylideneaminc]-acetic acid tert-butyl ester prepared in Example 59a (2.3 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile (1.9 g, 6.5 mmol) prepared in Example 26a, AgF (1.7 g, 13 mmol), and triethylamine (2.6 g, 26 mmol) in dichloromethane (100 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.9 g, 55%).
Example 59c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
= NH
=0 CI 101 \\NI
M. W. 475.39 C25H25C12FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 59b (1.9 g, 3.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.1 g,99%).
Example 59d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F OH
NH OH
soro 4111 CI
M. W. 562.51 C29H34C12FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 59c (0.6 g, 1 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.3 g, 2 mmol), HATU (0.6 g, 1.6 mmol) and iPr2NEt (0.9 g, 7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.4 g, 71%).
FIRMS (ES-) filh Ca'cc' for C29H3402FN303+ H )1: 562.2034. found: 562.2033.
Example 60a Preparation of intermediate rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester CI F0 0?c/
= NH
CI
M. W. 531.50 C29H33C12FN202 In preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester as described in Example 59b, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester was obtained as the second product: a white foam, Yield, 1 g, 29%.
Example 60b Preparation of intermediate rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid = NH
=\µ
ci M. W. 475.39 C25H25C12FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 60a (0.4 g, 0.75 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.46 g, 100%).
Example 60c Preparation of rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide OH
= NH ilk "or Nµ Vir CI
M. W. 562.51 C29H34C12FN303 In a manner similar to the method described in Example 42e, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 60b (0.45 g, 0.75 mmol) was reacted with 2-((S)-2,2-dimethy141,3]dioxolan-4-y1)-ethylamine (0.23 g, 1.6 mmol), HATU (0.45 g, 1.2 mmol) and iPr2NEt (0.9 g, 7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.4 g, 95%).
FIRMS (IS) m/z Cala for C29H34C12FN303 11 RNI 11)']: 562.2034, found:
562.2033, Example 61a Preparation of intermediate (Z)-2-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-pheny1)-acrylonitrile ci N
M. W. 304.18 C16H11C12N0 In a manner similar to the method described in Example lb, 4-chloro-2-methoxybenzyl cyanide (2 g, 10 mmol) prepared in Example 58a Step B was reacted vith 3-chlorobenzaldehyde (2 g, 14 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (50 mL) at 50 C for 5 h to give (Z)-2-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-acrylonitrile as a white powder (1.9 g, 63%).
Example 61b Preparation of intermediate rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI 0 02( M. W. 517.50 C28H34C12N203 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-acrylonitrile (1.8 g, 5.9 mmol) prepared in Example 61a, AgF (1.7 g, 13 mmol), and triethylamine (2.8 g, 28 mmol) in dichloromethane (100 mL) at room temperature for 24 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.8 g, 60%).
Example 61c Preparation of intermediate rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid = NH F OH
CI ON
M. W. 461.39 C24H26C12N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 61b (2 g, 3.9 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.2 g, 98%).
Example 6111 Preparation of rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI 0 N_../-{'OH
OH
1101 P'µ
M. W. 548.51 C28H35C12N304 In a manner similar to the method described in Examples 42c, 42d, rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 61c (0.2 g, 0.35 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1.0 mmol), HATU (0.24 g, 0.63 mmol) and iPr2NEt (0.3 mL, 1.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.15 g, 84%).
FIRMS (ES') raiz Calcd fi,r C281435C12N304 H [(M A-1YI: 548.2078, found:
548,2077.
Example 62a Preparation of intermediate (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(2,3-difluoro-pheny1)-acrylonitrile F
ci M. W. 293.68 C15H7C1F3N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (4.5 g, 26 mmol) was reacted wiih 2,3-difluorobenzaldehyde (Aldrich) (4.5 g, 32 mmol), methanolic solution (25 wt%) of sodium methoxide (6.3 g, 29 mmol) in methanol (135 mL) at 50 C for 3 h to give (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(2,3-difluoro-pheny1)-acrylonitrile as a white powder (6.85 g, 88%).
Example 62b Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester F F _O
kJK
NH
1.1 CI F N
M. W. 507.00 C27H30C1F3N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was roacted with (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(2,3-difluoro-pheny1)-acrylonitrile (2.3 g, 8 mmol) prepared in Example 62a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.8 g, 44%).
Example 62c Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid F F
NH FOH
F. 11 1101 µ`N
M. W. 450.89 C23H22C1F3N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 62b (1.8 g, 3.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2 g, 100%).
i l RAS (ES') ailz Caticd thr C23H22C1F3N202 i [( Niti- F1)1: 451.1395, hund 451.1394.
Example 62d Preparation of rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide F F
= NH OH
110%µ" \`=
CI
M. W. 538.01 C27H31C1F3N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 62c(0.47 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.49 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.26 g, 58%).
II R MS (ES) iniz Ca icd for C27H31 Cl2F2N303-1- H [( M-i- 1: 538.2079. found:
538.207'7.
Example 62e Preparation of (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide F F
=
OH NH
CI
M. W. 538.01 C27H31C1F3N303 Rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.22 g) was separated by chiral SFC chromatography to provide chiral-(2R,35,4R,55)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (87 mg, 40%) and chiral-(2S,3R,4S,5R)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (87 mg, 40%).
Example 63a Preparation of intermediate (Z)-3-(3-bromo-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile Br F
CI
M. W. 354.58 C15H7BrC1F2N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (1.39 g, 8.2 mmol) was reacted with 3-bromo-2-fluorobenzaldehyde (Apollo)(2 g, 9.9 mmol), methanolic solution (25 wt%) of sodium methoxide (2 g, 9 mmol) in methanol (40 mL) at 50 C
for 3 h to give (Z)-3-(3-bromo-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile as a white powder (2.3 g, 79%).
Example 63b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester Br F
=
IS ""
Cl FN
M. W. 567.91 C27H30BrC1F2N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3-bromo-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (2.3 g, 6.5 mmol) prepared in Example 63a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2 g, 54%).
Example 63c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Br F of0H
= NH F-.7c,OH
w 140 µµ
CI FN
M. W. 5 1 1.80 C23H22BrC1F2N202.C2HF302 In a manner similar to the method described in Example ld, rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 63b (2 g, 3.5 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.1 g, 95%).
FIRMS (ES ') miz Calcd for C23H22BrC1F2N2021 H [(Mit 1) F]: 511.0594, found:
51 1.0595.
Example 63d Preparation of rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Br F
NH OH
=N\
CI
M. W. 598.91 C27H31BrC1F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 63c (0.5 1 g, 0.83 mmol) was reacted ,Nith 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU
(0.57 g, 1.49 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.2 g, 40%).
HRMS (ES-) mlz Calcd for C27H31BrC1F2N303+ H RN1+H )1: 598.1278, found:
598.1278.
Example 63e Preparation of (2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Br F 0 NH OH
1101P' CI
M. W. 598.91 C27H31BrC1F2N303 Rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.15 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (66 mg, 44%) and chiral (2S,3R,4S,5R)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (70 mg, 47%).
Example 64a Preparation of intermediate (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-pheny1)-acrylonitrile CI
N
CI
M. W. 292.14 C151-18C12FN
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (4.5 g, 26 mmol) was reacted with 3-chlorobenzaldehyde (Aldrich) (4.4 g, 32 mmol), methanolic solution (25 wt%) of sodium methoxide (6.6 mL, 29 mmol) in methanol (150 mL) at 50 C for 3 h to give (Z)-2-(4-Chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-acrylonitrile as a white powder (6.5 g, 84%).
Example 64b Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI ic,(0.-2( =N
CI F N ¨
M. W. 505.46 C27H3102FN202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was routed with (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-acrylonitrile (2.3 g, 8 mmol) prepared in Example 64a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.02 g, 25%).
Example 64c Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI
1101µ"µw CI FN
M. W. 449.36 C23H23C12FN202.C2HF302 In a manner similar to the method described in Example ld, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 64b (1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.88 g, 79%).
H RAS (ES-) miz Cated for C23H23C12FN202+ H k rv1+1-0-1: 449. I 194, found:
449.1194.
Example 64d Preparation of rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide NH OH
Cl .' 1"F NµI\I
M. W. 536.47 C27H32C12FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 64c (0.46 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 48%).
II R MS (ES) iniz Ca icd for C27H32C12FN303 H [d 1: 536,1 878, fOulld:
5361877.
Example 64e Preparation of (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
= NH OH
1101 µ µ1\1 CI
M. W. 536.47 C27H32C12FN303 Rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.15 g) was separated by chiral SFC chromatography to provide chiral (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (71 mg, 47%) and chiral-(2S,3S,4S,5R)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (70 mg, 47%).
Example 65a Preparation of intermediate (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3-fluoro-phenyl)-acrylonitrile CI
M. W. 275.69 C15I-I8C1F2N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (3.27 g, 19 mmol) was roacted with 3-fluorobenzaldehyde (Aldrich) (2.87 g, 23 mmol), methanolic solution (25 wt%) of sodium methoxide (4.83 mL, 21 mmol) in methanol (90 mL) at 50 C for 3 h to give (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(3-fluoro-pheny1)-acrylonitrile as a white powder (5.2 g, 98%).
Example 65b Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-pheny1)-pyrrolidine-2-carboxylic acid tert-butyl ester F
= NH
Cl F -M. W. 489.01 C27H31C1F2N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(3-fluoro-pheny1)-acrylonitrile (2.2 g, 8 mmol) prepared in Example 65a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-pheny1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.02 g, 26%).
Example 65c Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-pheny1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid = NH
"
CI F\\K
M. W. 432.90 C23H23C1F2N202.C2HF302 In a manner similar to the method described in Example ld, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 65b (1 g, 2.1 mmol) was reactcd with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 88%).
FIRMS (ES m/z Calcd for C23H23C1F2N202 i [(1\1 ]: 433.1489, found: 433.147.
Example 65d Preparation of rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide F OH
410'NH OH
CI 1.1%µF \\N
M. W. 520.02 C27H32C1F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 65c (0.46 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-pheny1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 48%).
HRMS ES)( Calcd for C27H32C1F2N303-4- 1-1 [(M+11)']: 520.2173, found:
520.2171, Example 66a Preparation of intermediate (Z)-3-(3-bromo-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile Br CI
M. W. 336.59 C15H8BrC1FN
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (1.9 g, 11 mmol) was reacted with 3-bromobenzaldehyde (Aldrich) (1.57 mL, 13.4 mmol), methanolic solution (25 wt%) of sodium methoxide (2.8 mL, 12 mmol) in methanol (50 mL) at 50 C for 3 h to give (Z)-3-(3-bromo-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile as a white powder (2.3 g, 60%).
Example 66b Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester Br o0?( IS ""
Cl FN
M. W. 549.92 C27H31BrCIFN202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3-bromo-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (2 g, 5.9 mmol) prepared in Example 66a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.3 g, 40%).
Example 66c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Br 0,0H
NH
F.tOH
CI F
M. W. 493.81 C23H23BrC1FN202.C2}1F302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 66b (1.2 g, 2.2 mmol) was reacted wid/ trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.1 g, 83%).
HRMS (ES' ) 1111Z Calcd for C23H23BrC1FN202¨ H [11\4-41)1: 493,0688, found:
493.0688.
Example 66d Preparation of rac-(2R,3R,4R,5 S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Br OH
NH
C I
M. W. 580.92 C27H32BrC1FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 66c (0.5 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.49 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.26 g, 55%).
FIRMS (ES-) m/z aled for C27H32BrC1FN303 11 [(4-41) j: 580.1373, found:
580,1372.
Example 67a Preparation of intermediate rac-(2S,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester Br 0 OK
NH
40 \\
01 F,,, M. W. 549.92 C27H31BrCIFN202 In preparation of rac-(2R,3R,4R,5 S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as described in Example 66b, rac-(2S,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester was obtained as the second product: a white foam (1.2 g, 37%).
Example 67b Preparation of intermediate rac-(2S,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Br 0 OH
= NH
1101:1 Cl F
M. W. 493.81 C23H23BrC1FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2S,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 67a (1.3 g, 2.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.2 g, 83%).
FIRMS (ES-) miz Cated for C23H23BrC1FN202¨ H RN44-1)1: 493.0688, found:
493.0689.
Example 67c Preparation of rac-(2S,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Br 0 OH
OH
NH
01 .' 1"F NµI\I
M. W. 580.92 C27H32BrC1FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2S,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 67b (0.5 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.49 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2S,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 44%).
IIRMS (ES') mlz Ca icd for C27H32BrC1FN303-- H [(M-141)1: 580.1373, found:
580.1372.
Example 68a Preparation of intermediate (Z)-2-(4-Chloro-2-fluoro-pheny1)-3-(3,4-dichloro-pheny1)-acrylonitrile ci CI
=1\1 ci M. W. 326.59 C15H7C13FN
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenyl acetonitrile (4.5 g, 26 mmol) was reacted wiLh 3,4-dichlorobenzaldehyde (Aldrich) (5.5 g, 32 mmol), methanolic solution (25 wt%) of sodium methoxide (6.6 mL, 29 mmol) in methanol (150 mL) at 50 C for 3 h to give (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(3,4-dichloro-pheny1)-acrylonitrile as a white powder (6.5 g, 76%).
Example 68b Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI
CI 410, NH
CI F N
M. W. 539.91 C27H30C13FN202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was roacted with (Z)-2-(4-ehloro-2-fluoro-pheny1)-3-(3,4-dichloro-pheny1)-acrylonitrile (2.6 g, 8 mmol) prepared in Example 68a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rae-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-earboxylic acid tert-butyl ester as a white foam (1.7 g, 39%).
Example 68c Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI
CI = NH
F. 11 CI FN
M. W. 483.80 C23H22C13FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 68b (1.7 g, 3.1 mmol) was reacted with trifluoroacetic acid in diehloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.8 g, 96%).
Example 68d Preparation of rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI
OH
CI NH
[1011µ"
CI
M. W. 570.92 C27H31C13FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 68c (0.5 g, 0.84 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.28 g, 59%).
II R MS (ES) iniz Ca icd for C27H31C13FN303 H [(N.4-14)1: 570,1488, tbimd:
570.1489.
Example 69a Preparation of intermediate (Z)-3-(3-chloro-4-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile CI
F
N
M. W. 308.99 C15H7C12F2N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (3.3 g, 19 mmol) was reacted wi 4-chloro-3-fluoro-benzaldehyde (Aldrich) (3.65 g, 23 mmol), methanolic solution (25 wt%) of sodium methoxide (4.8 mL, 21 mmol) in methanol (90 mL) at 50 C for 3 h to give (Z)-3-(3-chloro-4-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile as a white powder (3 g, 50%).
Example 69b Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI 1eØ1 F 410, NH
101P' Cl FN
M. W. 523.46 C27H30C12F2N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was roacted with (Z)-3-(3-chloro-4-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 69a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1 g, 24%).
Example 69c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Cl 0 OH
= NH FOH
1101 .
CI FN
M. W. 467.35 C23H22C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 69b (1 g, 1.9 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 90%).
Example 69d Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide NHOH
Cl M. W. 554.46 C27H31C12F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 69c (0.28 g, 0.48 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.21 g, 1.44 mmol), HATU (0.33 g, 0.87 mmol) and iPr2NEt (0.42 mL, 2.4 mmol) in CH2C12 at room temperature for h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.18 g, 77%).
15 HR IS ES)( rniz Ca tat for C27H31C13FN303 H [d M-1-11) 554.1784, tbulld: 554.1785.
Example 69e Preparation of (2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
F =
NH OH
CI
M. W. 554.46 C27H31C12F2N303 Rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.14 g) was separated by chiral SFC chromatography to provide chiral (2R,3R,4R,55)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (61 mg, 44%) and chiral-(2S,3S,4S,5R)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (61 mg, 44%).
Example 70a Preparation of intermediate (Z)-3-(4-bromo-thiophen-2-y1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile Br \
N
M. W. 342.62 C13H6BrC1FNS
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (4.05 g, 24 mmol) was reacted with 4-bromo-2-thiophenecarboxaldehyde (Aldrich) (6.08 g, 29 mmol), methanolic solution (25 wt%) of sodium methoxide (6 mL, 26 mmol) in methanol (90 mL) at 50 C for 3 h to give (Z)-3-(4-bromo-thiophen-2-y1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile as a light yellow solid (5.2 g, 64%).
Example 70b Preparation of intermediate rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester Br 0,1;:;>( is I NH
\'µ
Cl FN
M. W. 555.94 C25H29BrC1FN202S
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(4-bromo-thiophen-2-y1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.7 g, 8 mmol) prepared in Example 70a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.9 g, 20%).
Example 70c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Br OH
I NH
1101 "
CI F N
M. W. 499.83 C21H21BrC1FN202S.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 70b (0.9 g, 1.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a light blue solid (0.9 g, 92%).
Example 70d Preparation of rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Br I NH OH
CI
M. W. 586.95 C25H30BrC1FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 70c (0.2 g, 0.33 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.14 g, 1 mmol), HATU
(0.22 g, 0.58 mmol) and iPr2NEt (0.28 mL, 1.63 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.15 g, 80%).
FIRMS (ES) 111/Z Caled for C25H30BrC1FN303¨ H Rivii-Fhl: 586.0937, found:
586.0935.
Example 71a Preparation of intermediate (Z)-2-(4-Chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-acrylonitrile Cl F
F
CI
M. W. 360.14 C16H7C12F4N
Step A
A mixture of 3-chloro-4-(trifluoromethyObenzyl alcohol (Synquest) (4.77 g, 23 mmol) and activated Mn02 (19.5 g, 230 mmol) in 1,2-dichlorethane (80 mL) was heated and stirred at 80 C
for 3 h. The mixture was cooled to room temperature and filtered through a short pad of celite.
The celite was washed with dichloromethane, and ethyl acetate. The filtrates were combined, concentrated, dried under reduced pressure to give 3-chloro-4-(trifluoromethyl)benzaldehyde as a light yellow oil (2.8 g, 60%).
Step B
In a manner similar to the method described in Example lb, 4-chloro-2-methylbenzyl cyanide (1.9 g, 11 mmol) was reacted with 3-chloro-4-(trifluoromethyl)benzaldehyde (2.8 g, 14 mmol), methanolic solution (25 wt%) of sodium methoxide (2.8 mL, 12 mmol) in methanol (50 mL) at 50 C for 5 h to give (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-acrylonitrile as a yellow solid (2.45 g, 61%).
Example 71b Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester FCI ?( F = NH
`µ
CI F r, ¨
M. W. 573.46 C281-130C12F4N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-acrylonitrile (2.5 g, 6.9 mmol) prepared in Example 71a, AgF (1 g, 8 mmol), and triethylamine (2.4 mL, 17 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 30%).
Example 70c Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Cl 0 OH
F
F - NH
00%µ"
CI FN
M. W. 517.35 C24H22C12F4N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 70b (1.2 g, 2.1 mmol) was reacted µNitli trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as solid (1.1 g, 83%).
Example 71d Preparation of (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Cl F = NH OH
M. W. 604.47 C28H31C12F4N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 71c (0.22 g, 0.35 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1.05 mmol), HATU (0.24 g, 0.63 mmol) and iPr2NEt (0.3 mL, 1.74 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-trifluoromethyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.14 g, 73%).
HRMS ES iz Caled for C28H31 Cl2F4N303 H [(4+1-1)']: 604.1752, found:
604.1748.
Example 72a Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide Cl = NH
1101""
Cl M. W. 554.46 C27H31C12F2N303 Step A
In a manner similar to the method described in Example 3a Step A to C, (4R)-(-)-4-(2-hydroxyethyl)-2,2-dimethy1-1,3-dioxolane (Aldrich) (4.91 g, 33.6 mmol) was reacted with methanesulfonyl chloride (3.12 mL, 40.3 mmol) and triethylamine (9.34 mL, 67 mmol) in dichloromethane, then reacted with NaN3 (10.7 g, 0.16 mol) in N,N-dimethylformamide, then treated with Pt02 and H2 (50 psi) in ethyl acetate to give 24(R)-2,2-dimethy141,3]dioxolan-4-y1)-ethylamine as a brown oil (4.4 g, 90% for three steps).
Step B
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 69c (0.2 g, 0.48 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1.0 mmol), HATU
(0.23 g, 0.62 mmol) and iPr2NEt (0.3 mL, 1.72 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide as a white solid (0.11 g, 74%).
1-IRMS (IS) miz Calcd for C27H3103FN3034-11 [(/1-1-H)]: 554.1784, [bind:
554.176.
Example 72b Preparation of (2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide Cl NHOH
" µ,µ
Cl M. W. 554.46 C27H31C12F2N303 Rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide (80 mg) was separated by chiral SFC chromatography to provide chiral (2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (35 mg, 44%) and chiral (25,3S,4S,5R)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (35 mg, 44%).
Example 73a Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide CI F
.NH OH
1101 µ
CI
M. W. 554.46 C27H31C12F2N303 In a manner similar to the method described in Example 72a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 53b (0.44 g, 0.769 mmol) was t-acted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.33 g, 2.3 mmol), HATU (0.52 g, 1.36 mmol) and iPr2NEt (0.66 mL, 3.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide as a white solid (0.29 g, 68%).
FIRMS (ES') ni/z. CaLc.d fi,r C27H31C12F2N303 H [( M I 1) ]: 554.1 784, fbund:
554.1783.
Example 73b Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide CI F
NH OH
1101P' Cl M. W. 554.46 C27H31C12F2N303 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide (0.28 g) was separated by chiral SFC chromatography to provide chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (109 mg, 39%) and chiral-(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (109 mg, 39%).
Example 74 Preparation of rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide Cl 0 NH OH
Cl M. W. 536.47 C27H32C12FN303 In a manner similar to the method described in Example 72a, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid (0.2 g, 0.36 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1.07 mmol), HATU (0.24 g, 0.64 mmol) and iPr2NEt (0.31 mL, 1.78 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 54%).
R. MS (ES') ni/z. CaLcd for C27H32C12FN303 1 [t M-11-01: 5:36,1878, fund:
5361880.
Example 75 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide CI F
NH OH
CI
M. W. 536.47 C27H32C12FN303 In a manner similar to the method described in Example 72a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid (0.2 g, 0.36mmol) was reacted wiLl/ 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1.07 mmol), HATU (0.24 g, 0.64 mmol) and iPr2NEt (0.31 g, 1.78 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 54%).
HRMS (ES') Calcd for C27H32C12FN303+1-1 [(Ni+H)l: 536.1878. found:
536.1880.
Example 76 Preparation of rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide Cl 0 OH
OH
NH
Cl 0 N
M. W. 548.51 C28H3502N304 In a manner similar to the method described in Example 72a, rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid (0.2 g, 0.35 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1.0 mmol), HATU (0.24 g, 0.63 mmol) and iPr2NEt (0.3 mL, 1.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 57%).
[IRAS (ES') raiz Cadcd for C281-135C12N304 1 1 [(M F11) j: 548.2078, found:
548,2074.
Example 77 Preparation of rac-(2R,3R,4R,5 S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide NH OH
CI
M. W. 518.48 C27H33C12N303 In a manner similar to the method described in Example 72a, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid (0.2 g, 0.37 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.159 g, 1.1 mmol), HATU (0.25 g, 0.66 mmol) and iPr2NEt (0.32 mL, 1.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide as a white solid (0.15 g, 81%).
HMIS (ES) miz ULU ibr C27H33C12N303 H [(Mi II) j: 518.1972, found: 518.1972.
Example 78a Preparation of intermediate [3,3,4-trimethyl-pent-(E)-ylideneamino]- acetic acid tert-butyl ester M. W. 241.38 C14H27NO2 Step A
To a solution of ethyl 3,3-dimethylacrylate (Aldrich) (6.98 g, 54 mmol) in anhydrous tetrahydrofuran (60 mL) was added chlorotrimethylsilane (12 mL, 70 mmol), CuI
(1.5 g, 8 mmol) under nitrogen. The mixture was stirred and the temperature was cooled to -20 C. To the stirring mixture was slowly added a tetrahydrofuran solution (2 N) if isopropylmagnesium chloride (40 mL, 80 mmol) during a period of 30 min while maitining the temperature below -10 C. After the addition was finished, the reaction mixture was gradually warmed to 0 C and stirred at 0 C for 3 h. Aqueous saturated NH4C1 solution was added to quench the reaction, and the mixture was extracted with ethyl acetate and ethyl ether. The organic layers were combined, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;20, 1;10) to give 3,3,4-trimethyl-pentanoic acid ethyl ester as a colorless oil (7 g, 75%).
Step B
To a solution of 3,3,4-trimethyl-pentanoic acid ethyl ester (7 g, 41 mmol) in anhydrous ethyl ether (100 mL) at 0 C was added a ethyl ether solution (1 M) of LiA1H4 (67 mL, 67 mmol) under nitrogen. The reaction mixture was stirred at 0 C for 1 h, then poured into a ice-water.
The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated to give 3,3,4-trimethyl-pentan-1-ol as a colorless oil (5.4 g, 100%).
Step C
To a solution of 3,3,4-trimethyl-pentan-l-ol (5.4 g, 41 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (22 gõ 52 mmol) The reaction mixture was stirred at room temperature for 3 h. Aqueous Na2S03 solution was added to quench the reaction.
The organic layers were separated, washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes=1:30) to give 3,3,4-trimethyl-pentanal as a colorless oil (Yield: 1.1 g, 21%).
Step D
In a manner similar to the method described in Example la, glycine tert-butyl ester (1g, 7.7 mmol) was reacted with 3,3,4-trimethyl-pentanal (i .1 gõ 8 filrnoi) in CH2C12 at room temperature for 5 h to give [3,3,4-trimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.5 g, 80%).
Example 78b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F cle0?( NH
sow.
M. W. 555.51 C29H34C12F2N202 In a manner similar to the method described in Example lc, [3,3,4-trimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 78a (1.5 g, 6.2 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (1.1 g, 3.5 mmol) prepared in Example 52a, AgF (1.2 g, 9.5 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 56%).
Example 78c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
NH FO
"
1.1 CI FN
M. W. 495.40 C25H26C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 78b (1.1 g, 2 mmol) was reactd with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (1.1 g, 91%).
Example 78d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI F
NHOH
1101P \N=
CI
M. W. 582.52 C29H35C12F2N303 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 78c (0.55 g, 0.9 mmol) was reactedvith 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.39 g, 2.7 mmol), HATU
(0.62 g, 1.6 mmol) and iPr2NEt (0.78 mL, 4.5 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.32 g, 62%).
H RMS (ES-) mlz Cated for C29H35C12F2N303,-- H [( M+1-1)1: 582.2097, found:
582.2095.
Example 78e Preparation of (2R,3S,4R,55)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide NHOH
1101P'µ
CI
M. W. 582.52 C29H35C12F2N303 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.25 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 40%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 40%).
Example 79a Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide CI F
NH OH CI
F
M. W. 582.52 C29H35C12F2N303 In a manner similar to the method described in Example 72a rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 78c (0.55 g, 0.9 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.39 g, 2.7 mmol), HATU (0.62 g, 1.6 mmol) and iPr2NEt (0.78 mL, 4.5 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide as a white solid (0.3 g, 58%).
FIRMS (ES') rwrz Cala' for C29H3502F2N303-,- H [0'0+H )]: 582.2097, found:
582.2094.
Example 79b Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide CI F OH
= N H OH
1101 µ
CI
M. W. 582.52 C29H35C12F2N303 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide (0.29 g) was separated by chiral SFC chromatography to provide chiral (2R,35,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.12 g, 41%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.12 g, 41%).
Example 80a Preparation of intermediate [3,3-dimethyl-pent-4-en-(E)-ylideneamino]-acetic acid tert-butyl ester M. W. 225.33 C13H23NO2 Step A
To a solution of methyl 3,3-dimethy1-4-pentenoate (Aldrich) (6.1 g, 43 mmol) in anhydrous ethyl ether (100 mL) at 0 C was added a tetrahydrofuran solution (2 M) of LiA1H4 (32 mL, 64 mmol) under nitrogen. The reaction mixture was stirred at 0 C for 1 h, then poured into a ice-water.
The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated to give 3,3-dimethyl-pent-4-en-1-ol as a colorless oil (4.8 g, 98%).
Step B
To a solution of oxalyl chloride (5.9 g, 46 mmol) (Aldrich) in dichloromethane (60 mL) at -78 C
was added the solution of dimethyl sulfoxide (6.6 mL, 92 mmol) in dichloromethane dropwise.
After 5 mins, the solution of 3,3-dimethyl-pent-4-en-l-ol (4.8 g, 42 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min.
Triethylamine (21 mL, 0.15 mol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. The water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3,3-dimethyl-pent-4-enal as a colorless oil (Yield: 3.2 g, 68%).
Step C. In a manner similar to the method described in Example la, glycine tert-butyl ester (1.3 g, 10 mmol) was t-acted with 3,3-dimethyl-pent-4-enal (I ,2 g, I I mnio I) in CH2C12 at room temperature for 18 h to give [3,3-dimethyl-pent-4-en-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.1 g, 93%).
Example 80b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F (:)/Cy =E NH
110(µ ,,, I
CI F\\
M. W. 535.47 C281-130C12F2N202 In a manner similar to the method described in Example lc, [3,3-dimethyl-pent-4-en-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 80a (2.1 g, 9.3 mmol) was reacted µ;µ,ii.1/ (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2 g, 6.4 mmol) prepared in Example 52a, AgF (0.9 g, 7.1 mmol), and triethylamine (1.5 g, 15 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.98 g, 56%).
Example 80c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Cl F 0/0H
= NH FO
"
CI FN
M. W. 479.36 C24H22C12F21\1202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 80b (1.0 g, 1.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.0 g, 91%).
Example 80d Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide CI F
= NH (31 101µµ"
CI F
M. W. 606.55 C311-135C12F2N303 In a manner similar to the method described in Example 42c, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 80c (1.0 g, 1.69 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.73 g, 5.0 mmol), HATU (1.15 g, 3 mmol) and iPr2NEt (1.46 mL, 8.4 mmol) in CH2C12 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide as a white solid (0.82 g, 80%).
Example 80e Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide = NH OH
OP
F
C
I
M. W. 566.47 C28H31C12F2N303 In a manner similar to the method described in Example42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 80d (0.36 g, 0.59 mmol) was reacted with aqueous HC1 solution (1 N, 1 mL) in tetrahydrofuran (10 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.32 g, 95%).
I RMS (ES') raiz Cated for C28H3102F2N303 1 [( M I 1)]: 566.1784, tbund:
566.1786.
Example 81a Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide Of NH
101""
CI
M. W. 608.56 C31H37C12F2N303 A suspension of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 80d (0.4 g, 0.65 mmol) and Pt02 (0.2 g) in ethyl acetate (15 mL) was vigorously shaken tinder 147 atornosphere (30 psi) for 1 h. The mixture was filtered through a short pad of celite, and the filtrate was concentrated to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide as a white gum (0.33 g, 83%).
Example 81b Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI F
.NH OH
1101 µ
CI
M. W. 568.49 C28H33C12F2N303 In a manner similar to the method described in Example 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 81a (0.41 g, 0.67 mmol) was reacted with aqueous HC1 solution (1 N, 1 mL) in tetrahydrofuran (10 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.38 g, 99%).
HRMS ES)( n1,17 Caled for C28H33C12F2N303-4- H [(Mi-1-l) ]: 568.1940, found: 568.1942.
Example 82a Preparation of intermediate [3-methy1-3-phenyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester M. W. 275.39 C17H25NO2 Step A
To a solution of 3-methy1-3-phenylbutanoic acid (ChemBridge) (4.46 g, 25 mmol) in anhydrous tetrahydrofuran (150 mL) at 0 C was added a tetrahydrofuran solution (1 M) of BH3.THF
(Aldrich, 50 mL, 50 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 3 h, then concentrated. The residue was partitoned between ethyl acetate and water. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated to give 3-methy1-3-phenyl-butan-1-ol as a colorless oil (4.1 g, 100%).
Step B
To a solution of oxalyl chloride (1.7 g, 13 mmol) (Aldrich) in dichloromethane (50 mL) at -78 C
was added the solution of dimethyl sulfoxide (1.9 mL, 27 mmol) in dichloromethane (10 mL) dropwise. After 5 mins, the solution of 3-methy1-3-phenyl-butan-l-ol (2 g, 12 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (6.1 mL, 44 mol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. The water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3-methyl-3-phenyl-butyraldehyde as a colorless oil (Yield: 1.8 g, 90%).
Step C
In a manner similar to the method described in Example la, glyeine tert-butyl ester (1.3 g, 10 mmol) was reacted with 3-methyl-3-phenyl-butyraldehyde (1.8 g, I 1 rornol) in CH2C12 at room temperature for 18 h to give [[3-methyl-3-phenyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.3 g, 93%).
Example 82b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-ehloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
o.O= 1\111H
M. W. 585.53 C32H32C12F2N202 In a manner similar to the method described in Example lc, [[3-methy1-3-phenyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 82a (2.3 g, 8.3 mmol) was reacted %Nit)/ (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.4 g, 7.7 mmol) prepared in Example 52a, AgF (0.7 g, 5.5mmol), and triethylamine (2.1 g, 21 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methyl-2-phenyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1 g, 22%).
Example 82c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Ci F
= NH FLÇO
F
CI F µN
M. W. 529.42 C28H24C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 82b (1.0 g, 1.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methy1-2-phenyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.0 g, 91%).
Example 82d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methyl-2-phenyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH OH
OP' *CI
M. W. 616.53 C32H33C12F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 82c (0.35 g, 0.54 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.24 g, 1.62 mmol), HATU (0.37 g, 0.98 mmol) and iPr2NEt (0.47 mL, 2.7 mmol) in CH2C12 at room temperature for h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methyl-2-phenyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.21 g, 66%).
20 FIRP,AS (ES Caled for C32H33C12F2N303 II [0,114-1)' j:
616.1940, found: 61 6 1939, Example 83a Preparation of intermediate (Z)-3-(3-chloro-5-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile ci ci 40 M. W. 308.99 C15H7C12F2N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (3.4 g, 20 mmol) was reacted with 3-chloro-5-fluoro-benzaldehyde (Aldrich) (3.77 g, 24 mmol), methanolic solution (25 wt%) of sodium methoxide (4.99 mL, 22 mmol) in methanol (90 mL) at 50 C for 3 h to give (Z)-3-(3-chloro-5-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile as a white powder (5.5 g, 90%).
Example 83b Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester CI ofiCy NH
F
CI F N
M. W. 523.46 C27H30C12F2N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-5-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 83a, AgF (1.0 g, 8 mmol), and triethylamine (2.8 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 29%).
Example 83c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI 10,0H
= NH FFOH
F
"
CI =F N
M. W. 467.35 C23H22C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 83b (1.2 g, 2.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.3 g, 97%).
Example 83d Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-phenyl)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI
= NH OH
F Ow' CI
M. W. 554.46 C27H31C12F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 83c (0.4 g, 0.69 mmol) was reacted ,vvith 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.3 g, 2.06 mmol), HATU
(0.47 g, 1.24 mmol) and iPr2NEt (0.6 mL, 3.44 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.13 g, 35%).
HRMS (ES-) miz Caled for C27H31 Cl3FN303+ H M+1-01: 554.1784, found: 554.1782.
Example 84a Preparation of intermediate (Z)-3- {2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl} -2-(4-chloro-2-fluoro-phenyl)-acrylonitrile -"F CI
CI
M. W. 466.46 C23H26C12FN 025i Step A
To a solution of 5-chlorosalicylaldehyde (2 g, 12.8 mmol) (Aldrich) in N,N-dimethylformamide (40 mL) was added K2CO3 (5.3 g, 38 mmo), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (3.67 g, 15 mmol, Aldrich). The reaction mixture was heated at 60 C for 18 h.
The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, concentrated, and the residue was purified by chromatography (Et0Ac:Hexanes=1:8, then 1:4) to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde as a brown oil (Yield 3.8 g, 91%).
Step B
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (1.7 g, 10 mmol) was reacted µNiill 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde (3.8 g, 12.5 mmol), methanolic solution (25 wt%) of sodium methoxide (2.5 mL, 11 mmol) in methanol (60 mL) at 50 C for 3 h to give (Z)-3- {242-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyll -2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a yellow oil (4.5 g, 80%).
Example 84b Preparation of intermediate rac-(2R,3S,4R,5S)-3- {2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro -phenyl} -4-(4-chloro -2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carboxylic acid tert-butyl ester 0 Ox' = NH
CI /10,0, CI F N
M. W. 679.78 C35H49C12FN204Si In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl} -2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (3.7 g, 8 mmol) prepared in Example 84a, AgF (1.0 g, 8 mmol), and triethylamine (2.8 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3- {2- [2-(tert-butyl-dimethyl-silanyloxy)-etho xy] -5-chloro -phenyl} -4-(4-chloro -2-fluor -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carboxylic acid tert-butyl ester as a white foam (1.0 g, 18%).
Example 84c Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-345-chloro-2-(2-hydroxy-ethoxy)-pheny1]-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid HO
0 (-1 OH
= NH
"
CI *u"
CI FN
M. W. 509.47 C25H27C12FN204.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(242-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenylI -4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 84b (1.0 g, 1.5 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-[5-chloro-2-(2-hydroxy-ethoxy)-pheny1]-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.9 g, 98%).
Example 84d Preparation of rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-[5-chloro-2-(2-hydroxy-ethoxy)-pheny1]-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide HO
OH
= NH
CI al \\N
LIW. F
M. W. 596.53 C29H36C12FN305 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-[5-chloro-2-(2-hydroxy-ethoxy)-pheny1]-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 84c (0.4 g, 0.64 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.28 g, 1.93 mmol), HATU (0.44 g, 1.15 mmol) and iPr2NEt (0.56 mL, 3.21 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-345-chloro-2-(2-hydroxy-ethoxy)-pheny1]-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (50 mg, 13%).
I R. MS (ES') raiz CaIed for C29H36C12FN305 I H [( [VII / 01: 596,2089, tbund:
596.2087.
Example 85a Preparation of intermediate (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-acrylonitrile oI Ati Cl 1.1 CI
M. W. 322.17 C16H10C12FN 0 In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (2.8 g, 16.6 mmol) was reacted with 5-chloro-2-methoxybenzaldehyde (Matrix) (3.4 g, 19.9 mmol), methanolic solution (25 wt%) of sodium methoxide (4.17 mL, 18 mmol) in methanol (100 mL) at 50 C for 3 h to give (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-acrylonitrile as a white solid (2.0 g, 37%).
Example 85b Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester NH
CI Ow CI F N
M. W. 535.49 C281133C12FN203 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (1.1 g, 5 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-acrylonitrile (1.28 g, 4 mmol) prepared in Example 85a, AgF (0.76 g, 6 mmol), and triethylamine (1.38 mL, 10 mmol) in dichloromethane (100 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.3 g, 14%).
Example 85c Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid NH
"
OH
CI 0 00"
CI F
M. W. 479.38 C24H25C12FN203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 85b (0.3 g, 0.56 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.32 g, 97%).
Example 85d Preparation of rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide OH
410' NH
ci ci F
M. W. 566.51 C28H34C12FN304 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 85c (0.32 g, 0.54 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.23 g, 1.62 mmol), HATU (0.37 g, 0.98 mmol) and iPr2NEt (0.47 mL, 2.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (65 mg, 21%).
FIRMS (ES') libiZ Calcd for C28H3402FN304+ I-1 [(11/44+1-1)1: 566.1983. found:
566.1984.
Example 86 Preparation of rac(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (quinolin-3-ylmethyl)-amide CI ON
= NH N
CI
M. W. 571.56 C33H32C12N40 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol) prepared in Example ld was reacted with quinolin-3-yl-methylamine (47.5 mg, 0.3 mmol), HATU (76.0 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight. to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (quinolin-3-ylmethyl)-amide (54.4 mg, 47.5 %) as a white powder.
HRMS (ES') TrbiZ Calcd for C33H32C12N40 + H [(1A+H)']: 571.2026, found:
571.2027.
Example 87 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 4-trifluoromethyl-benzylamide CI
=- NH
\\
C I
M. W. 588.498 C31f130C12F3N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted ,õ-vit1-14-trifluoromethylbenzyl amine (52.5 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 4-trifluoromethyl-benzylamide (58.1 mg, 58.04 %).
HRIMS (ES `) ntlz Caled for C311-130C12F3N30+ H [(M+HY I: 588.1791, found:
588.1788.
Example 88 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 3-trifluoromethyl-benzyl amide F F
CI
H
NH
M. W. 588.498 C31I-130C12F3N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 3-trifluoromethylbenzyl amine (52.55 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 3-trifluoromethyl-benzyl amide (26.2 mg, 26.2 %).
fiRMS (ES') rrik Ca led =for C311-130C12F3N30-i H [(NU II) ]: 588.179i, found:
588.1788.
Example 89 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 4-hydroxy-benzylamide CI
= NH OH
CI
M. W. 536.51 C30I-131C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 4-hydroxybenzyl amine (36.9 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 4-hydroxy-benzylamide (45.1 mg, 45.0 %).
FIRMS (ES-) 111/Z Ca'cc' for C301-131C12N302 4- H [(M+H)--): 536.1866, found:
536.1866.
Example 90 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 3-iodo-benzylamide CI
410. NH
CI
M. W. 646.393 C30H30C121N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 3-iodobenzyl amine (68.92 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 3-iodo-benzylamide (44.1 mg, 34.1 %).
FIRMS (ES') raiz Caled lbr C301-13002IN30 i RM I 1 Y1:646,0884, found:
646.0881.
Example 91 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-ethyl-butyl)-amide CI n NH
w*, CI
M. W. 514.54 C29H37C12N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 2-ethyl butyl amine (30.3 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-ethyl-butyl)-amide (34 mg, 33.04 %).
FIRMS (ES ') rwrz Calcd for C29H37C12N30 + H [(1V1-1-FI)]:5 14.2387, found:
514.2385.
Example 92 Preparation of rac-4- [(2R,3S ,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbonyl] -amino} -p ip eridine-1 -carboxylic acid tert-butyl ester )ro,ro r LYI
CI F
41 7. NH
0 ' Cl F N
M. W. 649.61 C33H40C12F2N403 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (1.8 g, 3.1 mmol) was reacted ,õ-vith 4-Amino-piperidine-1-carboxylic acid tert-butyl ester(Aldrich, 931 mg, 4.65 g, 4.65 mmol), HATU (2.12 g, 0.92 mmol) and iPr2NEt (2.7 mL, 15.5 mmol) in CH2C12 at room temperature overnight, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give a white solid (0.758 g, 38%).
FIRMS (ES ) m/z Calcd for C33H40C12F2N403 11 RM H j: 649.2519, found:
649.2518.
Example 93 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic acid r `Y) Ci F Hojc:
NH F F
CI F N
M. W. 549.49 C281-132C12F2N40. C2HF302 To a stirred solution of a mixture of TFA/CH2C12(5 mL/10 mL), rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyll-aminol-piperidine-1-carboxylic acid tert-butyl ester (example 92, 510 mg, 0.79 mmol) was added and the mixture was stirred at rt for 15 min. The solvent was removed and the residue dried to give a white solid after precipation from methylene chloride and ethyl acetate. 492 mg.
I R. MS (ES' ) raiz Ca Icd for C28H32C12F2N40 1 1 RM F II) j: 549.19()4, found: 549,1994, Example 94 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1-methanesulfonylpiperidin-4-y1)-amide rNi CI F
= NH
Cl FN
M. W. 627.58 C29H34C12F2N403S
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic acid (80 mg, 0.10 mmol) in methylene chloride (10 mL), methanesulfonyl chloride (14 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the misture was stirred at rt for 1 hr. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crued which was chromatographied on an ISCO machine (0-10% Et0Ac/CH2C12) to give a white solid. 53 mg.
HR MS (ES-) nIz Caled fir C29H34C12F2N403S H 627.1770, found: 627.1766.
Example 95 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1-methyl-carbonyl-piperidin-4-y1)-amide o (NI
CI F NH
w CI F N
M. W. 591.53 C30H34C12F2N403 To a stirred solution of (2R,3S,4R,5S)-3-(3-ehloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetie acid (80 mg, 0.10 mmol) in methylene chloride (10 mL), acetic anhydride (18 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the misture was stirred at rt for 1.5 hr. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crued which was chromatographied on an ISCO machine (0-10% Et0Ac/CH2C12) to give a white solid. 58 mg.
HRMS (ES-) miz Caled lig C301-13402F2N403,- H[( M+H)1: 591.2100, found:
591.2099.
Example 96 Preparation of rac-(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1-benzoyl-piperidin-4-y1)-amide o ç) CI F NH
= NH
10 CI F "N
M. W. 653.59 C35H36C12F2N402 To a stirred solution of (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic acid (80 mg, 0.10 mmol) in methylene chloride (10 mL), benzoyl chloride (21 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the misture was stirred at rt for 1 hr. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crued which was chromatographied on an ISCO machine (0-10% Et0Ac/CH2C12) to give a white solid. 36 mg. HRMS (ES') m/z Caled fir C35H36C12F2N402 H 4 I-1 )' j: 653.2256, found: 653.2253.
Example 97 Preparation of rac-4- { [(2R,3S ,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrro lidine-2-carbonyl] -amino} -p ip eridine-1-carboxylic acid isopropylamide I rN1 CI F NH
= NH
Cl F N
M. W. 634.60 C32H39C12F2N502 To a stirred solution of (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic (80 mg, 0.10 mmol) in methylene chloride (10 mL), 2-propyl isocyante (18 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the misture was stirred at rt for 1 h. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crued which was chromatographied on an ISCO machine (0-10% Et0Ac/CH2C12) to give a white solid.
R MS (1:,:S') rah Ca[cd for C32H39C12F2N502 H [(1v1-f-H)`]: 634.2520, found:
634.2522 Example 98a Preparation of intermediate (Z)-3-(5-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile F
1111111 Cl CI
M. W. 310.13 C15H7C12F2N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (2.8 g, 16.6 mmol) was reacted with 5-chloro-2-fluorobenzaldehyde (Alfa) (3.2 g, 19.9 mmol), methanolic solution (25 wt%) of sodium methoxide (4.17 mL, 18 mmol) in methanol (100 mL) at 50 C for 3 h to give (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-acrylonitrile as a off white solid (3.5 g, 68.6%).
Example 98b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester NH
CI
CI F N
M. W. 523.46 C27H30C12F2N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.2 g, 10 mmol) was routed with (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-acrylonitrile (2.46 g, 8 mmol) prepared in Example 98a, AgF (1.52 g, 12 mmol), and triethylamine (2.78 mL, 20 mmol) in dichloromethane (1500 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 26%).
Example 98c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid F n OH
== NH
"
CI
CI F N
M. W. 467.35 C23H22C12F 12N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 98b (1.1 g, 2.1 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.1 g, 90%).
Example 98d Preparation of rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide F
NH OH
CI ai M. W. 554.46 C27H31C12F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 98c (0.4 g, 0.68 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.3 g, 2.06 mmol), HATU
(0.47 g, 1.24 mmol) and iPr2NEt (0.6 mL, 3.44 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-eyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.36 g, 80%).
HR I\S ES)( Trilz Ca icd for C27H31C12F2N303-1- H [( 554.1784. found: 554.1782.
Example 99a Preparation of intermediate [3-cyclopropy1-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester 00y-U,v, M. W. 239.36 C14H25NO2 Step A
To a suspension of CuI (7.61 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) at -50 C was added cyclopropylmagnesium bromide (0.5 M, 160 mL, 80 mmol) during a period of 15 min.
After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to -50 C, a tetrahydrofuran solution (50 mL) of diethyl isopropylidenemalonate (Aldrich) (4 g, 20 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 3 h. Aqueous saturated NH4C1 solution was added to quench the reaction.
The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran.
The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;20, 1;10) to give 2-(1-cyclopropy1-1-methyl-ethyl)-malonic acid diethyl ester as a colorless oil (4.3 g, 89%).
Step B
To a solution of 2-(1-cyclopropy1-1-methyl-ethyl)-malonic acid diethyl ester (4.3 g, 17.8 mmol) in DMSO (30 mL) was added LiC1 (1.5 g, 35.6 mmol) and H20 (0.3 mL, 17.8 mmol).
The reaction mixture was heated at 170 C for 4 h, then poured into a ice-water, extracted with ethyl acetate. The organic layer were separated, washed with water, brine, dried over MgSO4, and concentrated to give 3-cyclopropy1-3-methyl-butyric acid ethyl ester as a colorless oil (2 g, 66%).
Step C
To a solution of 3-cyclopropy1-3-methyl-butyric acid ethyl ester (2 g, 11.75 mmol) in anhydrous tetrahydrofuran (40 mL) at 0 C was added a tetrhydrofuran solution (1 M) of LiA1H4 (23.5 mL, 23.5 mmol) under nitrogen. The reaction mixture was stirred at 0 C for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes = 1;10, 1:5) to give 3-cyclopropy1-3-methyl-butan-1-ol as a colorless oil (0.7 g, 46%).
Step D
To a solution of oxalyl chloride (0.75 g, 5.9 mmol) (Aldrich) in dichloromethane (30 mL) at -78 C was added the solution of dimethyl sulfoxide (0.84 mL, 11.8 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 3-cyclopropy1-3-methyl-butan-l-ol (0.69 g, 5.4 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (2.7 mL, 19.4 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3-cyclopropy1-3-methyl-butyraldehyde as a light yellow oil (Yield: 0.68 g, 98%).
Step E
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted vi.h 3-cyclopropy1-3-methyl-butyraldehyde (0.68 g, 5.3 F311nol) in CH2C12 at room temperature for 5 h to give [3-cyclopropy1-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.9 g, 75%).
Example 99b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropy1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid methyl ester CI F n ,ye = NH
\\
CI F N
M. W. 507.41 C26H26C12F2N202 To a solution of [3-cyclopropy1-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 99a (0.9 g, 3.76 mmol) and (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (1.16 g, 3.76 mmol) prepared in Example 52a in dichloromethane (100 mL) were added triethylamine (0.76 g, 7.5 mmol) and AgF (0.47 g, 3.76 mmol), in one portion. The mixture was stirred at room temperature for overnight. The mixture was then quenched with sat. NH4C1 and extracted with CH2C12. The organic phase was separated, filtered through celite and dried over Na2SO4, and concentrated. The residue was dissolved into methanol (40 mL), and DBU (3 mL) was added. The mixture was heated at 100 C
for 5 h, then cooled to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer were separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes = 1;5, 1:3) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropyl-2-methyl-propy1)-pyrrolidine-2-carboxylic acid methyl ester as a white foam (0.95 g, 50%).
Example 99c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropy1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid CI F OH
Oe=
410' NH
*I"
CI F N
M. W. 493.39 C25H24C12F2N202 To rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropy1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid methyl ester prepared in Example 99b (0.95 g, 1.87 mmol) in tetrahydrofuran (40 mL) was added an aqueous solution (20 mL) of NaOH (0.15 g, 3.7mmol) and methanol (20 mL). The reaction mixture was stirred at room temperature for 18 h. The "pH" of the mixture was adjusted to 5 by aqueous HC1 solution. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, concentrated, and trituated with dichloromethane and hexanes to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid as a white solid (0.78 g, 80%) Example 99d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropy1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI F OH
NH OH
CI \µI\I
M. W. 580.51 C29H33C12F2N303 In a manner similar to the method described in Examples 42e and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropyl-2-methyl-propy1)-pyrrolidine-2-carboxylic acid prepared in Example 99c (0.41 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.43 mL, 2.5 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropy1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.33 g, 70%).
FIRMS (ES )1111Z Cal for C29H33C12F2N303 1 RIM j: 580.1940, found: 580. i 936.
Example 99e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropyl-2-methyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH OH
1101P'Ippr CI
M. W. 580.51 C29H33C12F2N303 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.3 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropyl-2-methyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.11 g, 37%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropy1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.11 g, 37%).
HRMS (ES') rniz Calcd for C29H33Cl2F2N303+ H [(M+H)+1: 580.1940, found:
580.1941.
Example 100a Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-3-methyl-pheny1)-acrylonitrile CI
F
CI N
M. W. 306.17 C16H10C12FN
Step A
In a manner similar to the method described in Example 57 Step A, 4-chloro-2-methylbenzyl alcohol (PLATTE) (1.69 g, 11 mmol) was reacted with thionyl chloride (20 mL) to give 4-chloro-2-methylbenzyl chloride as a colorless oil (1.83 g, 97%).
Step B
In a manner similar to the method described in Example 57 Step B, 4-chloro-2-methylbenzyl chloride (1.83 g, 10 mmol) was reacted with KCN (1.76 g, 27 mmol) in ethanol (13 mL) and water (10 mL) at 100 C for 1 h to give 4-chloro-2-methylbenzyl cyanide as a yellow oil (1.2 g, 69%) Step C
In a manner similar to the method described in Example lb, 4-chloro-2-methylbenzyl cyanide (1.2 g, 7.2 mmol) was reacted lyvith 3-chloro-2-fluorobenzaldehyde (1.38 g, 8.7 mmol), methanolic solution (25 wt%) of sodium methoxide (1.82 mL, 8 mmol) in methanol (50 mL) at 50 C for 3 h to give (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-3-methyl-pheny1)-acrylonitrile as a white solid (2.0 g, 91%).
Example 100b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-3-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F oe0-2( NH
1101 µµ
Cl M. W. 519.49 C28H33C12N202 To a solution of [3-cyclopropy1-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (0.93 g, 7.3 mmol) and To a solution of [3-cyclopropy1-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 99a (1.6 g, 7.3 mmol) and (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.5 g, 4.9 mmol) prepared in Example 100a in dichloromethane (100 mL) were added triethylamine (1.7 g, 12 mmol) and AgF (0.9 g, 7.3mmol), in one portion. The mixture was stirred at room temperature for 18 h. The mixture was then quenched with sat. NH4C1 and extracted with CH2C12. The organic phase was separated, filtered through celite and dried over Na2SO4, and concentrated.
The residue was dissolved into tert-butanol (30 mL), and DBU (5 mL) was added.
The mixture was heated at 100 C for 18 h, then cooled to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer were separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes = 1;10, 1:5) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-3-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2 g, 80%).
Example 100c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-3-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F n OH
= NH F.4 OH
CI
M. W. 463.38 C24H25C12FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-3-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 100b (2.0 g, 3.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-3-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.88 g, 85%).
Example 100d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-3-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide = NH OH
CI
M. W. 550.50 C281434C12FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-3-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 100c (0.44 g, 0.76 mmol) was reacted wi(lt 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.33 g, 2.3 mmol), HATU
(0.52 g, 1.37 mmol) and iPr2NEt (0.66 mL, 3.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-3-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.26 g, 64%).
HRMS (ES-) mlz Calcd for C281-13402FN303+ H M+FIYI: 550.2034, found: 550.2034.
Example 101a Preparation of intermediate [2-(tetrahydro-pyran-4-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester N
I
M. W. 241.33 C13H23NO3 In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with (tetrahydro-pyran-4-y1)-acetaldehyde (Pharrnacore) (0.64 g, 5 minol) in CH2C12 at room temperature for 5 h to give [2-(tetrahydro-pyran-4-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.43 g, 33%).
Example 101b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F 00-1( = - NH o 101"µµ
CI FN
M. W. 551.47 C28H30C12F2N203 In a manner similar to the method described in Example 100b, [2-(tetrahydro-pyran-4-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 100a (0.43 g, 1.8 mmol) was reacted µ;µ,ii.1/ (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (0.31 g, 1 mmol) prepared in Example 52a, AgF (0.19 g, 1.5 mmol), and triethylamine (0.46 g, 4.5 mmol) in dichloromethane (50 mL) at room temperature for 18 h, followed by reaction with DBU in tert-butanol at 100 C for 8 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (0.45 g, 82%).
Example 101e Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
NH o CI FN
M. W. 495.36 C24H22C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 101b (0.45 g, 0.81 mmol) was reacied with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.4 g, 80%).
Example 101d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH OH
1101P' CI
M. W. 582.47 C281-131C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 101c (0.15 g, 0.25 mmol) was reacted ,vvith 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.11 g, 0.74 mmol), HATU (0.17 g, 0.44 mmol) and iPr2NEt (0.21 mL, 1.2 mmol) in CH2C12 at room temperature for h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as 15 a white solid (0.25 g, 80%).
HRMS (ES-) mlz Calcd for C281-131 Cl2F2N304-:- H [( M+1-1)1: 582.1733, found:
582.1731.
Example 102a Preparation of intermediate [2-(1-methyl-cyclohexyl)-eth-(E)-ylideneamino]-acetic acid tert-20 butyl ester I q0 M. W. 253.39 C151-127NO2 Step A.
To a suspension ofNaH (60%, 3 g, 74 mmol) in DME (100 mL) was added methyl (dimethoxyphosphonyl)acetate (Aldrich) (11.3 g, 61.8 mmol). The mixture was stirred at room temperature for 40 min, then cyclohexanone (6.07 g, 61.8 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. Aqueous saturated NH4C1 solution was added and the mixture was extracted with ethyl acetate twice. The organic layers were combined, dried over MgSO4, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;10) to give cyclohexylidene-acetic acid methyl ester as a colorless oil (6.4 g, 67%).
Similar transformation was reported by Bruckner, R. et al in Eur. J. Org.
Chem. 2006, 2119-2133 and the described procedures were used without modification.
Step B
To a suspension of CuI (7.61 g, 40 mmol) in anhydrous ethyl ether (20 mL) at 0 C was added an ethyl ether solution (1.6 M) of MeLi (50 mL, 80 mmol) The reaction mixture was stirred at 0 C for 10 min. The solvent was evaporated under reduced pressure, then dichloromethane (20 mL) was added under nitrogen at 0 C. The mixture was stirred for 5 min. The solvent was evaporated again. To the residue was added dichlormethane (20 mL), and the temperature of the mixture was lowered to -78 C. To the mixture was added chlorotrimethylsilane (4.3 g, 40 mmol) and a dichloromethane solution (20 mL) of cyclohexylidene-acetic acid methyl ester (3.1 g, 20 mmol). The reaction mixture was allowed to slowly warmed to 0 C and stirred for 1 h. Aqueous saturated NH4C1 solution was added to quench the reaction. The mixture was extracted with ethyl ether twice. The organic layers were combined, dried over MgSO4, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;5) to give (1-methyl-cyclohexyl)-acetic acid methyl ester as a colorless oil (3.3 g, 97%).
Similar transformation was reported by Yamamoto, Y. et al in Tetrahedron Letter 44 (2003), 4265-4266 and the described procedures were used without modification.
Step C
To a solution of (1-methyl-cyclohexyl)-acetic acid methyl ester (3.3 g, 19.4 mmol) in anhydrous tetrahydrofuran (50 mL) at 0 C was added a tetrhydrofuran solution (1 M) of LiA1H4 (29 mL, 29 mmol) under nitrogen. The reaction mixture was stirred at 0 C for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated.
The residue was purified by chromatography (Et0Ac:hexanes = 1:4) to give 2-(1-methyl-cyclohexyl)-ethano1 as a colorless oil (2.2 g, 80%).
Step fl To a solution of oxalyl chloride (2.18 g, 17.2 mmol) (Aldrich) in dichloromethane (12 mL) at -78 C was added the solution of dimethyl sulfoxide (2.44 mL, 34.3 mmol) in dichloromethane (8 mL) dropwise. After 5 mins, the solution of 2-(1-methyl-cyclohexyl)-ethanol (2.2 g, 15.6 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (7.8 mL, 56mmo1) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give (1-methyl-cyclohexyl)-acetaldehyde as a light yellow oil (Yield: 2 g, 91%).
Step E
In a manner similar to the method described in Example la, glycine tert-butyl ester (1.87 g, 14.3 mmol) was reacted with (1-methyl-cyclohexyl)-acetaldehyde (2.9 g, 14.3 ram I) in CH2C12 at room temperature for 18 h to give [2-(1-methyl-cyclohexyl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (3.4 g, 95%).
Example 102b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
= NH II
`µm M. W. 563.52 C30H34C12F2N202 In a manner similar to the method described in Example 100b, [2-(1-methyl-cyclohexyl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 101a (2.55 g, 10 mmol) was reacted µ.;vitl/ (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 52a, AgF (1.55 g, 12.3 mmol), and triethylamine (2.8 mL, 20 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (10 ml) in tert-butanol (50 mL) at 100 C for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow solid (3 g, 66%).
Example 102c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F OH
F
41' NH /10 µ`N
FOH
CI F ¨
M. W. 507.41 C26H26C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 102b (3 g, 5.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (3.3 g, 100%).
Example 102d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
OH
NH it lOr CI
M. W. 594.53 C30H35C12F2N303 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 102c (0.5 g, 0.8 mmol) was reacted ,vvith 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.35 g, 2.41 mmol), HATU (0.55 g, 1.45 mmol) and iPr2NEt (0.70 mL, 4.0 mmol) in CH2C12 at room temperature for h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a 15 white solid (0.22 g, 46%).
HRMS (ES-) miz Caled for C301-13502F2N303,- H[( M+1-1)]: 594.2097, found:
594.2094.
Example 102e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-20 cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH ik CI F N
M. W. 594.53 C30H35C12F2N303 Rac-(2R,3S,4R,5S)- 3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.18 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (78 mg, 71%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (80 mg, 73%).
FIRMS (IS) raiz Cala for C301-13502F2N303 ' II [0,11 I-1 )' j: 594.2097, found: 594:2094.
Example 103a Preparation of intermediate 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid benzyl ester j<ii, 0 el M. W. 333.43 C19H27N04 Step A
A mixture of 2,2-dimethylbutyrolactone (6.84 g, 60 mmol) and KOH (3.36 mmol) in H20 (60 mL) was heated at reflux for 2 h. The solution was cooled to room temperature and concentrated to dryness to give 4-hydroxy-2,2-dimethyl-butanoic acid monopotassium salt as a white solid (10.2 g, 100%).
Step B
To the mixture of 4-hydroxy-2,2-dimethyl-butanoic acid monopotassium salt (60 mmol) and benzyl bromide (8.55 mL, 72 mmol) were added NaI (10.8 g, 72 mmol) and K2CO3 (8.29 g, 60 mmol). The reaction mixture was stirred at reflux for 18 h. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by flash column chromatography (Et0Ac:
hexanes=1:2) to give 4-hydroxy-2,2-dimethyl-butyric acid benzyl ester as a colorless oil (9 g, 67%) The same transformations were reported in EP246529 and the described procedures were used without modification.
Step C
To a solution of oxalyl chloride (2.8 mL, 22 mmol) (Aldrich) in dichloromethane (40 mL) at -78 C was added the solution of dimethyl sulfoxide (3.1 mL, 44 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 4-hydroxy-2,2-dimethyl-butyric acid benzyl ester (4.5 g, 20 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (10 mL, 72 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 2,2-dimethy1-4-oxo-butyric acid benzyl ester as a colorless oil (Yield: 2.9 g, 66%).
Step D
In a manner similar to the method described in Example la, glycine tert-butyl ester (1.72 g, 13.2 mmol) was reacted with 2,2-dimethy1-4-oxo-butyric acid benzyl ester (4.1 g, 13.2 inmol) in CH2C12 at room temperature for 18 h to give 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid benzyl ester as a colorless oil (4.1 g, 93%).
Example 103b Preparation of intermediate rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
=NH
Cl 0 01 F N
M. W. 643.56 C34H34C12F2N204 In a manner similar to the method described in Example 100b, 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid benzyl ester prepared in Example 103a (4.1 g, 12.3 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 52a, AgF (1.55 g, 12.3 mmol), and triethylamine (2.5 g, 24 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (4 ml) in tert-butanol (40 mL) at 100 C for 4 h to give rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow gum (0.98 g, 19%).
Example 103c Preparation of intermediate rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid Fj OH
CI F of0H
NH
110"P0 Cl F N
M. W. 587.46 C30H2602F2N204.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 103b (0.98 g, 1.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white gum (0.94 g, 86%).
Example 103d Preparation of rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F n OH
NH
1101 F 0 *
M. W. 674.57 C34H35C12F2N305 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 103c (0.94 g, 1.34 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.58 g, 4.0 mmol), HATU (0.92 g, 2.41 mmol) and iPr2NEt (1.17 mL, 6.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.2 g, 22%).
[IRAS (ES') raiz Cacd for C34H35C12F2N305, 11 [( Mi ]: 074.1995, fbund:
674.1991.
Example 104a Preparation of intermediate 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid methyl ester M. W. 257.33 C13H23N04 Step A
A mixture of 2,2-dimethylbutyrolactone (6.84 g, 60 mmol) and KOH (3.36 g) in H20 (60 mL) was heated at reflux for 2 h. The solution was cooled to room temperature, and acidified to "pH"
5 with aqueous HC1 solution. The mixture was then extracted with ethyl acetate three times. The combined organic layers wer washed with brine, dried over MgSO4, concentrated under reduced pressure to give 4-hydroxy-2,2-dimethyl-butanoic acid as a colorless oil (4 g, 51%).
Step B
To the mixture of 4-hydroxy-2,2-dimethyl-butanoic acid (2.2 g, 16.6 mmol) in ethyl ether (16 mL) and methanol (24 mL) at 0 C was added a hexane solution (2.0 M) of trimethylsilyldiazomethane (Aldrich) (12.5 mL, 25mmo1). The reaction mixture was stirred at 0 C for 1 h. The solvents were evaporated. The residue was taken up in ethyl acetate, washed with diluted aqueous HC1 solution, saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give 4-hydroxy-2,2-dimethyl-butyric acid methyl ester as a colorless oil (1.5 g, 62%).
Step C
To a solution of oxalyl chloride (1.09 mL, 12.5 mmol) (Aldrich) in dichloromethane (20 mL) at -78 C was added the solution of dimethyl sulfoxide (1.77 mL, 25 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 4-hydroxy-2,2-dimethyl-butyric acid methyl ester (1.5 g, 11.3 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (5.7 mL, 41 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min.
Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 2,2-dimethy1-4-oxo-butyric acid methyl ester as a light yellow oil (Yield: 1.2 g, 81%).
Step D
In a manner similar to the method described in Example la, glycine tert-butyl ester (1.09 g, 8.32 mmol) was reacted with 2,2-dimethy1-4-oxo-butyric acid methyl ester (1.2 g, 8.32 11111101) in CH2C12 at room temperature for 18 h to give 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid methyl ester as a colorless oil (2.1 g, 100%).
Example 104b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methoxycarbony1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI
NH
'Js.
N,µ
Cl FN 0 M. W. 567.47 C281-130C12F2N204 In a manner similar to the method described in Example 100b, 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid methyl ester prepared in Example 104a (2.1 g, 8.3 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (2.05 g, 6.7 mmol) prepared in Example 52a, AgF (1.27 g, 10 mmol), and triethylamine (2.3 mL, 17 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (2 ml) in tert-butanol (10 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methoxycarbony1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (0.75 g, 20%).
Example 104c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
= NH
F.LOH
0, CI [10 N 0 M. W. 511.36 C24H22C12F2N204.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 104b (0.7 g, 1.23 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.75 g, 97%).
Example 104d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NHOH
1101 µ \\N 0 0.
CI
M. W. 598.47 C28H31C12F2N305 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenoxycarbonyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 104c (0.75 g, 1.26 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.52 g, 3.6 mmol), HATU (0.82 g, 2.16 mmol) and iPr2NEt (1.04 mL, 6 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methyl-2-phenoxycarbonyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.45 g, 56%).
FIRMS (ES ') rwrz Ca'cc' for C28H31C12F2N305-,- H [(M+H )1: 598.1682, found:
598.1679.
Example 105a Preparation of intermediate [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester oo an /
M. W. 343.59 C18H37NO3Si Step A
A mixture of 2,2-dimethyl-propane-1,3-diol (Aldrich) (10 g, 96 mmol) and imidazole (9.8 g, 140 mmol) in dichloromethane (200 mL) was added tert-butyldimethylchlorosilane (15.9 g, 10.6 mmol). The reactiom mixture was stirred at room temperature for 0.5 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with dichloromethane. The combined organic layers wer washed with brine, dried over MgSO4, concentrated to give 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propan-1-ol as a colorless oil (20.4 g, 97%).
Step B
To the solution of 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propan-1-ol (20.4 g, 93 mmol) and triethylamine (26 g, 186 mmol) in dichloromethane (200 mL) at 0 C
was added a dichlormethane solution (20 mL) of methanesulfonyl chloride (Aldrich) (8.69 mL, 112 mmol).
The reaction mixture was stirred at 0 C for 2 h. Water was added. Organic layer was separated, the aqueous layer was extracted with dichlormethane. The combined organic layers were washed with diluted aqueous HC1 solution, saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give methanesulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propyl ester as a yellow oil (24 g, 87%).
Step C
To the solution of methanesulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propyl ester (5 g, 16.8 mmol) in anhydrous dimethyl sulfoxide (50 mL) was added KCN
(2.85 g, 44 mmol). The reaction mixture was heated at 120 C for 16 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes = 1;4) to give 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyronitrile as a yellow oil (2.2 g, 57%).
Step D
To a solution of 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyronitrile (2.2 g, 9.67 mmol) (Aldrich) in dichloromethane (20 mL) at -78 C was added a toluene solution (1 M) of DIBAL
(10.6 mL, 10.6 mmol) dropwise. The reaction mixture was stirred at 0 C for 3 h. The mixture was poured into aqueous saturated NH4C1 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1:4) to give 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyraldehyde as a colorless oil (Yield: 0.84 g, 38%).
Step E
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.52 g, 3.64 mmol) was reacted wih 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyraldehyde (0.84 g, 3.64 mmol) in CH2C12 at room temperature for 18 h to give [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.25 g, 100%).
Example 105b Preparation of intermediate rac-(2R,3S,4R,5S)-5-[3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
NH
1101 µ`Ni M. W. 653.72 C33H44C12F2N203Si In a manner similar to the method described in Example 100b, [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 105a (1.25 g, 3.64 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (0.93 g, 3 mmol) prepared in Example 52a, AgF
(0.57 g, 4.5 mmol), and triethylamine (1.05 mL, 7.5 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (3.6 ml) in tert-butanol (15 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-5-[3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (1.2 g, 61%).
Example 105c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F 0.e0H
NH
F
OH
110 `µki CI F
M. W. 483.35 C23H22C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-543-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 105b (1.1g, 1.68 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 100%).
Example 105d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide NH OH
1101P'OH
CI
M. W. 570.46 C27H31C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 105c (1 g, 1.67 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.73 g, 5 mmol), HATU (1.14 g, 3 mmol) and iPr2NEt (1.46 mL, 8.4 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.3 g, 64%).
HRMS (ES') MIZ Calcd for C27H31 Cl2F2N304 H [(M+H)1: 570.1733, found:
570.1731.
Example 105e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
= NHOH
1101 µOH
CI
M. W. 570.46 C27H31C12F2N304 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.24 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (102 mg, 43%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (93 mg, 39%).
FIRMS (ES ITIPZ Caled for C27H31 Cl2F2N304 II [GNI-WY]: 570.173:3, found:
570.1730, Example 106a Preparation of intermediate [3,3-diethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester 00y-Nk M. W. 255.40 C15H29NO2 Step A
To a solution of dimethyl malonate (10 g, 75mmol), 3-pentanone (6.5 g, 75 mmol) and pyridine (7.9 g, 100 mmol) in anhydrous tetrahydrofuran (300 mL) at 0 C was added a dichloromethane solution (1 M) of TiC14 (100 mL, 100 mmol) during a period of 1 h. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 18 h.
Water was added to quench the reaction. The mixture was extracted with ethyl ether. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate.
The organic layers were combined, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;20) to give 2-(1-ethyl-propylidene)-malonic acid dimethyl ester as a light yellow oil (7 g, 46%).
Step B
To a suspension of Cul (7.61 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) at -50 C was added ethylmagnesium chloride (2 M, 40 mL, 80 mmol) during a period of 15 min.
After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to -50 C, a tetrahydrofuran solution (50 mL) of 2-(1-ethyl-propylidene)-malonic acid dimethyl ester (3.5 g, 17.5 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 3 h. Aqueous saturated NH4C1 solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;30) to give 2-(1,1-diethyl-propy1)-malonic acid dimethyl ester as a colorless oil (2.6 g, 57%).
Step C
To a solution of 2-(1,1-diethyl-propy1)-malonic acid dimethyl ester (2.5 g, 11 mmol) in DMSO
(30 mL) was added LiC1 (0.91 g, 21.6 mmol) and H20 (0.19 mL, 11 mmol). The reaction mixture was heated at 170 C for 4 h, then poured into a ice-water, extracted with ethyl acetate.
The organic layer were separated, washed with water, brine, dried over MgSO4, and concentrated to give 3,3-diethyl-pentanoic acid methyl ester as a yellow oil (1.9 g, 100%).
Step D
To a solution of 3,3-diethyl-pentanoic acid methyl ester (1.9 g, 11 mmol) in anhydrous tetrahydrofuran (50 mL) at 0 C was added a tetrhydrofuran solution (2 M) of LiA1H4 (9 mL, 18 mmol) under nitrogen. The reaction mixture was stirred at 0 C for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated to give 3,3-diethyl-pentan-1-ol as a yellow oil (1.4 g, 90%).
Step E
To a solution of oxalyl chloride (0.86 mL, 9.9 mmol) (Aldrich) in dichloromethane (20 mL) at -78 C was added the solution of dimethyl sulfoxide (1.4 mL, 19.8 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 3,3-diethyl-pentan-l-ol (1.3 g, 9 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (4.5 mL, 32 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3,3-diethyl-pentanal as a yellow oil (Yield: 1 g, 78%).
Step F
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.92 g, 7 mmol) was reticied with 3,3-diethyl-pentanal (I g, 7 J111 nol) in CH2C12 at room temperature for 5 h to give [3,3-diethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.8 g, 100%).
Example 106b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
O2O= : NH
1101"' CI F N
M. W. 507.41 C26H26C12F2N202 In a manner similar to the method described in Example 100b, [3,3-diethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 106a (1.8 g, 7 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.74 g, 5.6 mmol) prepared in Example 52a, AgF (1.1 g, 8.6mmol), and triethylamine (1.95 mL, 14 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (7 ml) in tert-butanol (30 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white gum (1.8 g, 57%).
Example 106c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F 0.e0H
= NH
F.LOH
[10 CI F N
M. W. 509.43 C26H28C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 106b (1.8 g, 3.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a light yellow solid (2 g, 100%).
Example 106d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide NH OH
1101"' CI
M. W. 596.54 C30H37C12F2N303 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 106c (0.5 g, 0.8 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.35 g, 2.4 mmol), HATU (0.55 g, 1.4 mmol) and iPr2NEt (0.7 mL, 4 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.33 g, 70%).
HIS (ES') raiz Cadcd for C301137C12F2N3031 H [( 596,2253, lbund: 596.2254.
Example 107a Preparation of intermediate [3-ethy1-3-methyl-pent-(E)-ylidenea mino]-acetic acid tert-butyl ester I
M. W. 241.38 C14H27NO2 Step A
To a suspension of CuI (5.7 g, 30 mmol) in anhydrous tetrahydrofuran (100 mL) at -50 C was added methylmagnesium chloride (3 M, 20 mL, 60 mmol) during a period of 15 min. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to -50 C, a tetrahydrofuran solution (20 mL) of 2-(1-ethyl-propylidene)-malonic acid dimethyl ester (3 g, 15 mmol) prepared in Example 106a Step A was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 1 h. Aqueous saturated NH4C1 solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;30) to give 2-(1-ethyl-1-methyl-propyl)-malonic acid dimethyl ester as a colorless oil (3 g, 93%).
Step B
To a solution of 2-(1-ethyl-l-methyl-propy1)-malonic acid dimethyl ester (3 g, 14 mmol) in DMSO (30 mL) was added LiC1 (1.2 g, 28 mmol) and H20 (0.25 mL, 14 mmol). The reaction mixture was heated at 170 C for 3 h, then poured into a ice-water, extracted with ethyl acetate.
The organic layer were separated, washed with water, brine, dried over MgSO4, and concentrated to give 3-ethyl-3-methyl-pentanoic acid methyl ester as a yellow oil (1.5 g, 68%).
Step C
To a solution of 3-ethy1-3-methyl-pentanoic acid methyl ester (1.5 g, 9.4 mmol) in anhydrous tetrahydrofuran (30 mL) at 0 C was added a tetrhydrofuran solution (2 M) of LiA1H4 (5 mL, 10 mmol) under nitrogen. The reaction mixture was stirred at 0 C for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated to give 3-ethy1-3-methyl-pentan-1-ol as a yellow oil (1.3 g, 100%).
Step D
To a solution of oxalyl chloride (0.96 mL, 11 mmol) (Aldrich) in dichloromethane (20 mL) at -78 C was added the solution of dimethyl sulfoxide (1.56 mL, 22 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 3-ethy1-3-methyl-pentan-l-ol (1.3 g, 10 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (5 mL, 36 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3-ethyl-3-methyl-pentanal as a light yellow oil (Yield: 1 g, 78%).
Step F
In a manner similar to the method described in Example la, glycine tert-butyl ester (1.0 g, 7.8 mmol) was reacted with 3-ethyl-3-methyl-pentanal I g, 7,8 trimoi) in CH2C12 at room temperature for 5 h to give [3-ethyl-3-methyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.9 g, 100%).
Example 107b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethy1-2-methyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI
= : NH
CI FN
M. W. 551.51 C29H34C12F2N202 In a manner similar to the method described in Example 100b, [3-ethyl-3-methyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 107a (1.9 g, 7.8 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (1.9 g, 6.2 mmol) prepared in Example 52a, AgF (1.2 g, 9.4 mmol), and triethylamine (2.1 mL, 15 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (7 ml) in tert-butanol (30 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethyl-2-methyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow gum (2.5 g, 74%).
Example 107c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethyl-2-methyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F 0.e0H
F. 110 [101 CI F N
M. W. 495.40 C25H26C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethyl-2-methyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 107b (1.8 g, 3.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethyl-2-methyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a light yellow solid (2.5 g, 91%).
Example 107d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethy1-2-methyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide NH OH
1101P \µ=
CI
M. W. 582.52 C29H35C12F2N303 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethyl-2-methyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 106c (0.6 g, 1 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.43 g, 3 mmol), HATU (0.67 g, 1.8 mmol) and iPr2NEt (0.86 mL, 4.9 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethyl-2-methyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.3 g, 53%).
FIRMS (ES-) m/z Caled for C29H35C12F2N303 II [0,1111)' j: 582.2097, found:
582.2096, Example 108a Preparation of intermediate (Z)-2-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-2-fluoro-pheny1)-acrylonitrile CI
F
401 -1\1 CI
M. W. 328.12 C15H6C12F3N
Step A
To the solution of 4-chloro-2,6-difluorobenzyl bromide (Alfa) (2.5 g, 10 mmol) in ethanol (13 mL) and H20 (10 mL) was added KCN (1.75 g, 27 mmol). The reaction mixture was heated at 100 C for 1 h. The mixture was cooled, and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes = 1;4) to give (4-chloro-2,6-difluoro-pheny1)-acetonitrile as a yellow oil (1.1 g, 57%).
Step B
In a manner similar to the method described in Example lb, (4-chloro-2,6-difluoro-pheny1)-acetonitrile (1.1 g, 6 mmol) was reacted with 2-fluoro-3-chlorobenzaldehyde (1.2 g, 7mmol), methanolic solution (25 wt%) of sodium methoxide (1.5 mL, 7 mmol) in methanol (40 mL) at 50 C for 3 h to give (Z)-2-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-2-fluoro-pheny1)-acrylonitrile as a white solid (1.5 g, 75%).
Example 108b Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI 1c,(0?c/
410' NH
F
CI 111' F N
M. W. 505.46 C27H31C12FN202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (1 g, 5 mmol) was reacted with (Z)-2-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-2-fluoro-pheny1)-acrylonitrile (1.3 g, 4mmo1) prepared in Example 109a, AgF (0.77 g, 6 mmol), and triethylamine (1.4 mL, 10 mmol) in dichloromethane (120 mL) at room temperature for 18 h, followed by the reaction with DBU
(4.8 ml) in tert-butanol (20 mL) at 100 C for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white gum (0.9 g, 41%).
Example 108c Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI 0,0H
= NH
F ralõõ
W
Cl 11WP F
M. W. 467.35 C23H22C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 108b (0.9 g, 1.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.9 g, 91%).
Example 108d Preparation of rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
NHOH
\\N
M. W. 572.45 C27H30C12F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 108c (0.4 g, 0.67 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.29 g, 2 mmol), HATU
(0.46 g, 1.2 mmol) and iPr2NEt (0.58 mL, 3.3 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 77%).
HIS (ES-) mlz Cated for C27H3002F2N303,-- H[( M+1-1)1: 572.1689, found:
572.1691.
Example 109a Preparation of intermediate (Z)-2-(4-chloro-2,5-difluoro-pheny1)-3-(3-chloro-2-fluoro-pheny1)-acrylonitrile CI
F
N
:
M. W. 328.12 C15H6C12F3N
Step A
To the solution of 4-chloro-2,5-difluorobenzoic acid (Oakwood) (6.08 g, 31 mmol) in anhydrous tetrahydrofuran (75 mL) at 0 C was added a solution of BH3.THF (1 M, 62 mL, 62 mmol). The reaction mixture was stirred at room temperature for 18 h. Aqueous HC1 solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give (4-chloro-2,5-difluoro-pheny1)-methanol as a colorless oil (5.5 g, 98%).
Step B
A mixture of (4-chloro-2,5-difluoro-pheny1)-methanol (5.5 g, 32 mmol) in thionyl chloride (25 mL) was heated at refluxing (100 C) for 30 min. The mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous NaHCO3 solution, water, brine, dried over MgSO4, and concentrated to give 1-chloro-4-chloromethy1-2,5-difluoro-benzene as a yellow oil (2.1 g, 34%).
Step C
To the solution of 1-chloro-4-chloromethy1-2,5-difluoro-benzene (2.1 g, 11 mmol) in ethanol (13 mL) and H20 (10 mL) was added KCN (1.8 g, 28 mmol). The reaction mixture was heated at 100 C for 1 h. The mixture was cooled, and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Achexanes = 1;4) to give 4-chloro-2,5-difluoro-pheny1)-acetonitrile as a light yellow oil (1.0 g, 50%).
Step fl In a manner similar to the method described in Example lb, 4-chloro-2,5-difluoro-phenyl)-acetonitrile (1.0 g, 5 mmol) was reacted with 2-fluoro-3-ch1orobenza1dehyde (1.0 g, 6 mmol), methanolic solution (25 wt%) of sodium methoxide (1.3 mL, 5.9 mmol) in methanol (40 mL) at 50 C for 3 h to give (Z)-2-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-acrylonitrile as a white solid (1.3 g, 75%).
Example 109b Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-pheny1)-3-(3-ehloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI 1c,e0K
NH
F
Cl M. W. 505.46 C27H31C12FN202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (5 mmol) was reacted with give (Z)-2-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-2-fluoro-pheny1)-acrylonitrile (1.3 g, 3 mmol) prepared in Example 109a, AgF (0.77 g, 6 mmol), and triethylamine (1.4 mL, 10 mmol) in dichloromethane (120 mL) at room temperature for 18 h, followed by the reaction with DBU
(4.8 ml) in tert-butanol (20 mL) at 100 C for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylie acid tert-butyl ester as a light yellow gum (1.5 g, 69%).
Example 109c Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI
= NH FFOH
F "
M. W. 467.35 C23H22C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 109b (1.5 g, 2.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (1.5 g, 91%).
Example 109d Preparation of rac-(2R,3R,4R,5 S)-4-(4-chloro-2,5-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
= NHOH
F
F
CI
M. W. 572.45 C27H30C12F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 108c (0.5 g, 0.84 mmol) was reaeLed with 24(S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.73 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 50%).
FIRMS (ES') rcilz Calcd fi,r C27H30C12F2N3034 H [( M-i- II)]: 572.1689, thund:
572.1689.
Example 110a Preparation of intermediate [4-methoxy-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester 00y-N
1 o*.
M. W. 243.35 C13H25NO3 Step A.
A mixture of 2,2-dimethyl-propane-1,3-diol (Aldrich) (5 g, 48 mmol) in anhydrous ethyl ether (100 mL) at 0 C was added thionyl chloride (8.7 mL, 120 mmol). The reactiom mixture was stirred at 0 C for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl ether. The combined organic layers wer washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, concentrated to give 5,5-dimethyl-[1,3,2]dioxathiane 2-oxide as a light pink oil (4.8 g, 82%).
Step B
To the solution of 5,5-dimethyl-[1,3,2]dioxathiane 2-oxide (4.8 g, 39 mmol) in anhydrous dimethyl sulfoxide (50 mL) was added NaCN (5.8 g, 118 mmol). The reaction mixture was heated at 120 C for 5 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes = 1;4) to give 4-hydroxy-3,3-dimethyl-butyronitrile as a yellow oil (1.6 g, 38%).
Step C
To the solution of 4-hydroxy-3,3-dimethyl-butyronitrile (0.8 g, 7 mmol) in anhydrous dimethylformamide (5 mL) was added NaH (60%, 0.42 g, 11 mmol). The mixture was stirred at room temperature for 15 min, then iodomethane (0.88 mL, 14 mmol) was added.
The mixture was stiired at room temperature for 1 h. Water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, and concentrated to give 4-methoxy-3,3-dimethyl-butyronitrile as a yellow oil (0.85 g, 94%).
Step fl To a solution of 4-methoxy-3,3-dimethyl-butyronitrile (0.85 g, 6.7 mmol) in dichloromethane (20 mL) at -78 C was added a toluene solution (1 M) of DIBAL (7.4 mL, 7.4 mmol) dropwise.
The reaction mixture was stirred at 0 C for 1 h. The mixture was poured into aqueous saturated NH4C1 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to give 4-methoxy-3,3-dimethyl-butyraldehyde as a colorless oil (Yield: 0.3 g, 34%).
Step E
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.3 g, 2.3 mmol) was reacted with 4-methoxy-3,3-dimethyl-butyraldehyde (0.3 g, 2.3 1 nol) in CH2C12 at room temperature for 18 h to give [4-methoxy-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.56 g, 100%).
Example 110b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
NH
1101""
CI F N
M. W. 553.48 C28H32C12F2N203 In a manner similar to the method described in Example 100b, [4-methoxy-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 110a (3.8 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (0.94 g, 3 mmol) prepared in Example 52a, AgF (0.58 g, 4.6 mmol), and triethylamine (1.06 mL, 7.6 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (3.6 ml) in tert-butanol (20 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow solid (1 g, 59%).
Example 110c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
= NH FOH
F. 11 [10 CI F N
M. W. 497.37 C24H24C12F21\1203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 105b (1.0 g, 1.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (0.9 g, 82%).
Example 110d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NHOH
1101 µ0 \\
CI F
N
M. W. 584.49 C28I-133C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 110c (0.45 g, 0.74 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.32 g, 2.2 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (0.64 mL, 3.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.28 g, 65%).
FIRMS (ES-) rwrz Calcd for C281-133C12F2N304* H [(M+H )1: 584.1889, found:
584.1 X9O.
Example 110e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH OH
1101P'0 CI
M. W. 584.49 C281-133C12F2N304 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.24 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (114 mg, 48%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (114 mg, 48%).
FIRMS (ES-) ITI/Z Calcd for C281-133C12F2N304* H [(M+H )1: 584.1889, found:
584.1892.
Example 111a Preparation of intermediate 3-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester OO) I
a /
M. W. 371.64 C201--141NO3Si Step A
A mixture of 2,2-diethyl-propane-1,3-diol (Aldrich) (5.5 g, 40 mmo1) in anhydrous ethyl ether (100 mL) at 0 C was added thionyl chloride (10.6 g, 90 mmol). The reactiom mixture was stirred at 0 C for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl ether. The combined organic layers wer washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, concentrated to give 5,5-diethyl41,3,2]dioxathiane 2-oxide as a colorless oil (7 g, 98%).
Step B
To the solution of 5,5-diethyl-[1,3,2]dioxathiane 2-oxide (7 g, 39 mmol) in anhydrous dimethyl sulfoxide (40 mL) was added NaCN (3.9 g, 80mmol). The reaction mixture was heated at 120 C
for 20 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes = 1;2) to give 3-ethyl-3-hydroxymethyl-pentanenitrile as a yellow oil (1.7 g, 31%).
Step C
To the solution of 3-ethy1-3-hydroxymethyl-pentanenitrile (1.7 g, 12 mmol) and imidazole (1.2 g, 18 mmol) in dichloromethane (80 mL) was added tert-butyldimethylchlorosilane (2 g, 13 mmol).
The reactiom mixture was stirred at room temperature for 2 h. Water was added.
The organic layer was separated, the aqueous layer was then extracted with dichloromethane. The combined organic layers wer washed with brine, dried over MgSO4, concentrated to give 3-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-pentanenitrile as a colorless oil (2.28 g, 74%).
Step D
To a solution of 3-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-pentanenitrile (2.28 g, 8.9 mmol) in dichloromethane (20 mL) at -78 C was added a toluene solution (1 M) of DIBAL (9.8 mL, 9.8 mmol) dropwise. The reaction mixture was stirred at 0 C for 1 h. The mixture was poured into aqueous saturated NH4C1 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to give 3-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-pentanal as a colorless oil (Yield: 1.5 g, 65%).
Step E
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.78 g, 5.8 mmol) was reacted with 3-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-pentanal (1 .5 g, 5.8 mrnol) in CH2C12 at room temperature for 18 h to give [4-methoxy-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.2 g, 100%).
Example 111b Preparation of intermediate rac-(2R,3S,4R,5S)-5-[2-(tert-butyl-dimethyl-silanyloxymethyl)-2-ethyl-buty1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
= NH
Cl F N
--f-M. W. 681.77 C35H48C12F2N203Si In a manner similar to the method described in Example 100b, give [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 111a (2.2 g, 5.8 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.43 g, 4.6 mmol) prepared in Example 52a, AgF (0.89 g, 7 mmol), and triethylamine (1.6 mL, 12 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (7 ml) in tert-butanol (20 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-5-[2-(tert-butyl-dimethyl-silanyloxymethyl)-2-ethyl-buty1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow solid (1.8 g, 58%).
Example 111e Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethy1-2-hydroxymethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Ci F \ OH
= NH
u OH
CI F N
M. W. 511.40 C25H26C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-542-(tert-butyl-dimethyl-silanyloxymethyl)-2-ethyl-buty1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 111b (1.8 g, 2.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethyl-2-hydroxymethyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a light yellow solid (1.5 g, 94%).
Example 111d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethy1-2-hydroxymethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH OH
1101P'OH
CI
M. W. 598.51 C29H35C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethyl-2-hydroxymethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 111c (1.1 g, 1.8 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.78 g, 5 mmol), HATU (1.2 g, 3 mmol) and iPr2NEt (1.6 mL, 9 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethy1-2-hydroxymethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.11 g, 10%).
FIRMS (ES') Tri/z (Cacd for C29H35C12F2N304H- H [( H)]: 598.2046, fbund:
598.2045.
Example 112a Preparation of intermediate [2-(3-methyl-oxetan-3-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester 00?
M. W. 227.31 C12H21NO3 Step A
To a solution of 3-methy1-3-oxetanemethano1 (Aldrich) (3.5 g, 34 mmol) and triethylamine (10 g, 103 mmol) in dichloromethane (100 mL) at 0 C was added a dichlormethane solution (20 mL) of methanesulfonyl chloride (Aldrich) (5.08 g, 45 mmol). The reaction mixture was stirred at 0 C for 2 h. Water was added. Organic layer was separated, the aqueous layer was extracted with dichlormethane. The combined organic layers were washed with diluted aqueous HC1 solution, saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give methanesulfonic acid 3-methyl-oxetan-3-ylmethyl ester as a yellow oil (6 g, 97%).
Step B
To the solution of methanesulfonic acid 3-methyl-oxetan-3-ylmethyl ester (6 g, 33 mmol) in anhydrous dimethyl sulfoxide (30 mL) was added NaCN (3.2 g, 67 mmol). The reaction mixture was heated at 130 C for 3 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give (3-methyl-oxetan-3-y1)-acetonitrile as a yellow oil (2.5 g, 68%).
Step C
To a solution of (3-methyl-oxetan-3-y1)-acetonitrile (2.5 g, 22.5 mmol) in dichloromethane (30 mL) at -78 C was added a toluene solution (1 M) of DIBAL (24.7 mL, 24.7 mmol) dropwise.
The reaction mixture was stirred at 0 C for 3 h. The mixture was poured into aqueous saturated NH4C1 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to give (3-methyl-oxetan-3-y1)-acetaldehyde as a colorless oil (Yield: 0.8 g, 31%).
Step D
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.92 g, 7 mmol) was reacted iffi (3-methyl-oxetan-3-y1)-acetaldehyde (0.8 g, 7 J111 non in CH2C12 at room temperature for 18 h to give [2-(3-methyl-oxetan-3-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.6 g, 100%).
0,O,R R-"'N
RC---NH R1 R2 2 3 ),I1 Reagents and conditions: R is tert-butyl or methyl (1) If R1 or R2 is H, CH2C12, room temperature, overnight;
(2) If R1 and R2 are both not H, ethanol, 100 oC, 48 h;
Scheme 1 An intermediate of formula III can be made from a base-catalyzed condensation reaction of appropriately selected substituted-phenyl acetonitrile and aldehyde The reaction proceedes in a highly stereoselective manner with Z-isomer as the major or exclusive product.
Y 401 `1%1 + R)LR
X X
Reagents and conditions:
If R5 is H, aq. NaOH, iPrOH, room temperature, 5 min or Na0Me, Me0H, 50 C, 3 h Scheme 2 As illustrated in Scheme 3, pyrrolidine of formula IV can be made from intermediates II and III
by a convergent 1,3-dipolar cylcoaddition reaction mediated by lewis acid AgF
and triethylamine.
The [2+3] cycloaddition reactions of azomethine ylides 1,3-dipoles with olefinic dipolarphiles to form pyrrolidine ring formation have been described in published procedures including Jorgensen, K. A. et al (Org. Lett. 2005, Vol 7, No. 21, 4569-4572), Grigg, R.
et al (Tetrahedron, 1992, Vol 48, No. 47, 10431-10442; Tetrahedron, 2002, Vol 58, 1719-1737), Schreiber, S. L. et al (J. Am. Chem. Soc., 2003, 125, 10174-10175), and Carretero, J. C. et al (Tetrahedron, 2007, 63, 6587-6602).. Compounds IV is subsequently converted to acid V followed by amide formation with various amines using HATU as the coupling reagent to give the compounds of formula I. The amide formation from V to I can also be achieved under other conditions using EDCI and HOBt or oxalyl chloride as the coupling reagent to activate the acid V.
P\
0 0- R5 R4 N , õI R a RR4 R3 N + ). R
..'"i\T _______________________________________________________ Y 401 N1 X X
II III IV
N
b R4 N
R2 C R4 N , R5 im.
x Ri R5 -1'2 Y 0 \ NRl Y 0 \X
X N
X
V I
Reagents and conditions:
a. AgF, NE-t2, CH2C12 or C1CH2CH2C1, rt, 18 h;
b. 1) If R is tert-butyl, conc. H2SO4; or TFA, CH2C12, rt, 18 h;
or 2) If R is methyl, NaOH or Li0H, H20 and Me0H and THF, rt, 18 h;
c. HNR6R7, HATU, iPr2NEt, CH2C12, rt, 18 h Scheme 3 10 The process according to scheme 3 forms a further embodiment according to the present invention.
The pyrrolidine compounds I, IV, V are prepared initially as a racemic mixture and can be chirally separated using chiral Super Fluid Chromatography (SFC) or chiral HPLC or chiral 15 column chromatography. For example, racemic mixture of compound Ia and Ia' can be readily resolved into two optically pure or enriched chiral enantiomers by separation using chiral Super Fluid Chromatography (SFC). (Scheme 4).
R
R R
R
N¨R7 i 6 N¨R N¨IoR7 R
0 = 3 N¨R7 R 7 0 Z 3 0 a, . ' 11 1 =::. H
0=1.. R3H ' H R4 N
R
Re,. N.0 R2 + R5,4...
_...\,., N chiral separationR.4,µ R
N
' . ' R
, R 5 =õ== Ri ...0 \ 1 y N x X
X
la la' la la' racemic mixture chiral chiral Scheme 4 Examples The compounds of the present invention may be synthesized according to known techniques. The following examples and references are provided to aid the understanding of the present invention, the true scope of which is set forth in the appended claims.
Example la Preparation of intermediate [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester f)() N
M. W. 213.32 C 1 2H23N0 2 A mixture of glycine tert-butyl ester ( Alfa) (2.71 g, 20.0 mmol) and 3,3-dimethyl-butyraldehyde (Alfa) (2.21 g, 21.0 mmol) in CH2C12 (50 mL) was stirred at rt overnight. The reaction mixture was concentrated and the residue was dried in vacuo to give [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (4.29 g, 100%) as colorless oil which was used in the next step without further purification.
Example lb Preparation of intermediate (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile ci 40 c, '1\1 R05302754-000 CI
CI
5 M. W. 274.2 C15H9C12N
Method A.
To a solution of 4-chlorobenzyl cyanide (5.62 g, 4.00 mmol) and 3-chloro-benzaldehyde (Aldrich) (6.06 g, 4.00 mmol) in iPrOH (250 mL) was added 4 N NaOH (5 mL) dropwise at rt and the reaction mixture was stirred at rt for 10 min to give a white suspension. The solid was 10 filtered and washed with water and iPrOH and then dried overnight in vacuum to give (Z)-3-(3-chloro-pheny1)-2-(4-chloro-phenyl)-acrylonitrile (9.33 g, 85.1%) as a white powder which was used in the next step without further purification.
Method B.
15 To a solution of 4-chlorobenzyl cyanide (Aldrich) (4.5 g, 30 mmol) and 3-chloro-benzaldehyde (Aldrich) (4 g, 29 mmol) in methanol (150 mL) was slowly added a methanolic solution (Aldrich, 25 wt.%) of sodium methoxide (10 mL, 44 mmol). The reaction mixture was heated and stirred at 50 C for 3 h. The mixture became cloudy, and was cooled to room temperarure and filtered.
The white precipitate was washed with water, cold methanol, and then dried in vacu to give the 20 first batch of desired product (5.5 g). The filtrate was concentrated, diluted with water, neutralized by aqueous HC1 solution to "pH" 7, then extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac;hexanes = 1;20, then 1:10) to give the second batch of the desired product (1.6 g).The two batches were combined to give (Z)-3-(3-chloro-pheny1)-2-(4-chloro-25 phenyl)-acrylonitrile as a white powder (7.1 g, 88%).
1-11-0/1S (ES--) Calcd for C15H9C12N Psi Ft 273.0112; found: 273.0113.
Example le Preparation of intermediate rac-(2R,3R,4R,55)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI (:).,0?(' M. W. 487.5 C27H32C12N202 To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (4.26 g, 20.00 mmol) and (Z)-3-(3-chloro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile (5.48 g, 20.00 mmol) in C1CH2CH2C1 (100 mL) were added triethyl amine (4.2 g, 40.00 mmol) and AgF
(2.53 g, 20.00 mmol) in one portion. The mixture was stirred at rt overnight. The mixture was then quenched with sat. NH4C1 and extracted with CH2C12. The organic phase was separated, filtered through Celite and dried over Na2SO4. The mixture was then separated and concentrated.
The residue was triturated with Et0Ac and nHexane, and the precipitates were collected by filtration and the mother liquid was concentrated and further purified by flash column (Si02, 1-20% of Et0Ac in hexanes) to give rac-(2R,3R,4R,55)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester (6.65 g, 68.2%; FIRMS (ES) miz Cala' for C27H32C12N202 + H [(M+H) ]: 4.7. 1914, found: 487 1910) and rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (0.86 g, 8.8%).
HR.N4S (ES') rah Ca[cd for C27H32C12N202 F [(1\141-1)']: 487.1014, found:
487.1910).
Example ld Preparation of intermediate rac-(2R,3R,4R,55)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid Cl c,OH
= NH
CI
M. W. 431.4 C23H24C12N202 A solution of rac-(2R,3R,4R,55)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (3.78 g, 7.75 mmol) in conc.
H2504 (20 mL) was stirred at rt for 2 hrs. The mixture was then poured into ice and extracted with Et0Ac. The organic phase was separated, dried over Na2SO4, and concentrated. The residue was then triturated with Et0Ac and nHexane and the precipitates were collected by filtration and washed with ether to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3.60 g, 100%) as a white solid which was used in the next step without further purification:11RMS ( ES ') miz, Caled for C23H24C12N202 I
[(1\4 11)1: 431.1288, found: 431.1287.
Example le Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide Cl=
NH
CI-Cw"
M. W. 543.5 C29H36C12N402 A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol), 2-morpholin-4-yl-ethylamine (36.0 mg, 0.28 mmol), 2-(7-azabenzotriazo1-1-y1)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2C12 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by Si02 flash column (20-100% of Et0Ac in Hexanes) to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (60.5 mg, 86.4%) as a white amorphous.
H RAS (ES') Trilz. Calcd. for C29H36C12N402 1--1 [0,1-F-I-1)']; 543.2288, found: 523.2284.
Example lf Preparation of (2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide Cl Of = NH
,sµ
M. W. 543.5 C29H36C12N402 The racemic product obtained above (Example le, 45 mg) was further separated by SFC chiral column to give-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (13.1 mg, 29.1%) and (2S,3S,4S,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethylpropy1)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (14.6 mg, 32.4%).
Example 2 5 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid dimethylamide CI N
0.e NH
µµN
CI
M. W. 458.4 C23H29C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-10 pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example ld was reacted with dimethylamine (1.0 M in THF, 2 mL), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid dimethyl amide (57.8 mg, 90.0 %).
15 HRIVIS (ES-) mlz Cated fig C25H29C12N302 H [(1\1+H)-1: 458.1761, found:
458.1757.
Example 3a Preparation of intermediate 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine 0¨ft 20 M. W. 145.20 C7H15NO2 Step A.
To a solution of (4S)-(+)-4-(2-hydroxyethyl)-2,2-dimethy1-1,3-dioxolane (Aldrich) (21.1 g, 0.14 mol) and triethylamine (40 mL, 0.28 mol) in dichloromethane (250 mL) at 0 C
was added methanesulfonyl chloride (13.4 mL, 0.17 mol) dropwise. The reaction mixture was stirred at 0 C
25 for 1.5 h, then water was added. The organic layer was separated, washed with water, brine, dried over MgSO4, concentrated to give methanesulfonic acid 2-((S)-2,2-dimethy141,3]dioxolan-4-y1)-ethyl ester as a yellow oil (31.7 g, 98%).
Step B.
30 To a solution of methanesulfonic acid 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl ester (31.7 g, 0.14 mol) in N,N-dimethylformamide (200 mL) was added NaN3 (46 g, 0.71 mol).
The reaction mixture was stirred at room temperature for 70 h. Then the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine several times, dried over MgSO4, concentrated to give (S)-4-(2-azido-ethyl)-2,2-dimethyl-[1,3]dioxolane as a yellow oil (21.3 g, 88%).
Step C.
A suspension of (S)-4-(2-azido-ethyl)-2,2-dimethyl-[1,3]dioxolane as a yellow oil (18.7 g, 0.11 mol) and Pt02 (2.5 g) in ethyl acetate (100 mL) was vigorously shaken in a Parr under atmosphere of H2 (50 psi) for 18 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine as a colorless oil (14 g, 88%).
Example 3h Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Cl NH OH
\ N
CI
M. W. 518.5 C27H33C12N303 A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (431.4 mg, 1.00 mmol) prepared in Example ld, 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (217.5 mg, 1.5 mmol), HATU
(570.30 mg, 1.50 mmol) and iPr2NEt (258.6 mg, 2.00 mmol) in CH2C12 (20 mL) was stirred at rt for 1 hour.
The mixture was then diluted with CH2C12 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and the residue was treated with PPTS (cat) in Me0H (20 mL) at 120 C for 5 min with CEM
microwave reactor.
The reaction mixture was concentrated and the residue was diluted with Et0Ac and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4.
The mixture was then concentrated and purified by Si02 flash column (5% of Me0H in Et0Ac) to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (450.0 mg, 86.7%) as a white amorphous.
tIRMS (ES--) C.aled {by C27H33C12N303-t 11 [1M 518.1972, found:
518.1970.
Example 3c Preparation of (2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide Cl CI
M. W. 518.5 C27H33C12N303 The racemic product obtained above (Example 3b, 450.0 mg) was further separated by SFC
chiral column to give (2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (178.6 mg, 34.4%) and (2S,3S,45,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (159.8 mg, 30.8%).
Example 4 Preparation of rac-(2S,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-544-(2-morpholin-4-y1-2-oxo-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile ci N
NH CO) C
I
M. W. 626.6 C35H41C12N503 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example ld was reacted with 1-morpholin-4-y1-2-piperazin-1-yl-ethanone (65.0 mg, 0.30 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-5-[4-(2-morpholin-4-y1-2-oxo-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile (45.5 mg, 51.9 %).
FIRMS (ES ')1:11/Z Calcd for C35H41C12N503-:- H [(1'+H)1: 626.2659, found:
626.2654.
Example 5 Preparation of rac-(2S,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propy1)-544-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile 0,,k) w NH
=µµ
CI
M. W. 610.6 C33H41C12N502 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example ld was reacted with 2-piperazin-1-y1-1-pyrrolidin-1-yl-ethanone (65.0 mg, 0.33 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-Chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-5-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazine-l-carbonyl]-pyrrolidine-3-carbonitrile (60.5 mg, 70.8 %).
RAS (ES') atiz Caticd fbr C33H41C12N502-i- 11 )']: 610.271 0, found:
610.2708.
Example 6 Preparation of rac-(2S,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-544-(2-hydroxy-ethyl)-piperazine-1-carbonyll-pyrrolidine-3-carbonitrile cl 0,Nõ) NH
Cl' M. W. 543.5 C29H36C12N402 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example ld was reactod with 2-piperazin-1-yl-ethanol (65.0 mg, 0.50 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propy1)-5-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile (48.3 mg, 63.5 %).
HRIMS (ES') libiZ Cala' for C29H36C12N402-i- H [(M-F-H) ]: 543.2288, found:
543.2284.
Example 7 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (4-hydroxy-butyl)-amide Cl NH
= NH
CI
M. W. 502.4 C27H33C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example ld was reacted wit h 4-methylamino-butan-1-ol (44.5 mg, 0.50 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydroxy-butyl)-amide (30.5 mg, 43.4 %). FIRMS (ES') m/z Calcd tbr C27H33C12N302+11 [(M+I-I) j:
502.2023, found:
502.2020.
Example 8 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide CI
= NH LJ
Cl' M. W. 527.5 C29H36C12N40 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (82.2 mg, 0.20 mmol) prepared in Example ld was reacted with 2-pyrrolidin-1-yl-ethylamine (34.2 mg, 0.30 mmol), HATU (76.0 mg, 0.20 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (50.6 mg, 64.0 %). FIRMS (ES' ) Calcd for C29H36C12N40 +H [( M I 101: 527.2339, found: 527.2338.
Example 9 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-piperazin-1-yl-ethyl)-amide CI
NH
CI
5 M. W. 542.6 C29H37C12N50 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (82.2 mg, 0.20 mmol) prepared in Example ld was reacted with 2-piperazin-1-yl-ethylamine (38.7 mg, 0.30 mmol), HATU (76.0 mg, 0.20 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in 10 CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-piperazin-1-yl-ethyl)-amide (45.9 mg, 58.0 %). HRIAS (ES) rn/z Calcd for C29H37C12N50 +H [(M+H)+]:
542.2448, found: 542.24 zi 5 .
15 Example 10a Preparation of (S)-2- {[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyTamino1-3-methyl-butyric acid tert-butyl ester ci - NH3_ µN
M. W. 586.6 C32H41C12N303 20 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (215.7 mg, 0.50 mmol) prepared in Example ld was reacted with (S)-2-amino-3-methyl-butyric acid tert-butyl ester (125.4 mg, 0.60 mmol), HATU (210.1.0 mg, 0.60 mmol) and iPr2NEt (129.3 mg, 1.00 mmol) in CH2C12 (5 mL) at rt overnight to give (S)-2-1[(2R,3R,4R,5S)-3-(3-chloro-25 pheny1)-4-(4-chloro -pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrro lidine-2-carbonyl]-aminoI-3-methyl-butyric acid tert-butyl ester (95.0 mg, 32.4 %) after column separation. FIRMS (.[S) rniz Calcd for C32H41C12N303+14 [(NI+H)1: 586.2602, found: 586.2598.
Example 10b Preparation of (S)-2- [(2S,3S,4S ,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-aminoI-3-methyl-butyric acid tert-butyl ester b 0 NH y_ µ' CI N
M. W. 586.6 C32H41C12N303 Column separation from the above example (Example 10a) gave (S)-2-{[(2S,3S,4S,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyll-amino}-3-methyl-butyric acid tert-butyl ester (98.0 mg, 33.4 %).
HRMS (ES) ratz Calcd for C32H41 Cl2N303 H [(M+H)']: 586.2601, found: 586.2598, Example 10c Preparation of (S)-2- { [(2R,3R,4R,5 S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-aminoI-3-methyl-butyric acid methyl ester CI NH
=NHo R
M. W. 544.5 C29H35C12N303 Column separation from the above example (Example 10a) gave a mixture of (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyll-amino1-3-methyl-butyric acid tert-butyl ester and (S)-{[(2S,35,45,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid tert-butyl ester (45.8 mg, 15.6 %). The mixture was treated with 2N H2504 (catalytic) in Me0H (1 mL) at 120 C for 10 min using CEM
microwave reactor to give after purification by PR-HPLC: (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-aminoI-3-methyl-butyric acid methyl ester (15.5 mg, 36.5%).
FIRMS (ES- ) 1:11/Z Calcd for C29H35C12N303+1 [(N1+11)1: 544.2128, found:
544.2127, Example 10d Preparation of (S)-2- [(2S,3 S,4S ,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyli-aminoI-3-methyl-butyric acid methyl ester Clbo CI A-M. W. 544.5 C29H35C12N303 Column separation from the above example (Example 10a) gave a mixture of (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyll-amino1-3-methyl-butyric acid tert-butyl ester and (S)-{[(2S,35,45,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid tert-butyl ester (45.8 mg, 15.6 %). The mixture was treated with 2N H2504 (catalytic) in Me0H (1 mL) at 120 C for 10 min using CEM
microwave reactor to give after purification by reverse phase chromatography (20-95% of MeCN/water): (S)-2- {[(2S,3 S,4 S,5R)-3 -(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-aminoI-3-methyl-butyric acid methyl ester (13.5 mg, 31.8%).
HRMS (ES') MIZ Calcd for C29H35C12N303+H [(11/4v1+H)l: 544.2128. found:
544.2126.
Example 11 Preparation of (S)-2- [(2R,3R,4R,5 S)-3 -(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-amino -3 -methyl-butyric acid =
-;
NHo 40' CI
M. W. 530.5 C28H33C12N303 A mixture of (S)-2- { [(2R,3R,4R,5 S)-3 -(3 -chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carbony1]-aminoI-3-methyl-butyric acid tert-butyl ester (86.0 mg, 0.15 mmol) prepared in Example 10a and 2 N H2504 (0.5 mL) in MeCN (1 mL) was heated to 120 C for 10 min with CEM microwave reactor. The mixture was then concentrated and the residue was purified by reverse phase chromatography (20-95% of MECN/water) to give: (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyll-amino1-3-methyl-butyric acid (45.1 mg, 58.0%).
HRMS (ES' )1111Z Calcd for C28H33C12N303+H [(11/4,4+H)1: 530,1972. found:
530.1971.
Example 12 Preparation of (S)-2- [(2S,3S,4S ,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrro lidine-2-carbony1]-aminoI-3 -methyl-butyric acid 01v_a N
(j14,, CI lel M. W. 530.5 C28H33C12N303 A mixture of (S)-2-1[(2S,3S,4S,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-aminoI-3-methyl-butyric acid tert-butyl ester (90 mg, 0.15 mmol) prepared in Example 10b and 2 N H2SO4 (0.5 mL) in MeCN (1 mL) was heated to 120 C for 10 min with CEM microwave reactor. The mixture was then concentrated and the residue was purified by reverse phase chromatography (20-95% of MeCN/water) to give: (S)-2-{[(2S,3S,4S,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyll-amino1-3-methyl-butyric acid (45.8 mg, 56.3%).
iIf'S (ES') nth CaIed for C28H33C12N303+1-1 [d M I 101: 530,1972, tbund:
530.1971.
Example 13 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclopropylmethyp-amide CI
CI
M. W. 514.50 C28H33C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol) prepared in Example ld, (1-aminomethyl-cyclopropy1)-methanol (30.3 mg, 0.3 mmol), HATU (76.0 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2C12 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of MeCN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclopropylmethyl)-amide (23.9 mg, 24.7 %) as a white powder.
[IRAS (ES') raiz CaJcd kir C28I-13302N302 H [(M F j: 514.2023, found:
514.2024.
Example 14 Preparation of rac-(2R,3R,4R,5S)-3-(3-Chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclobutylmethyl)-amide CI QOH
NH
µµ, CI
M. W. 528.53 C29H35C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reactd with (1-aminomethyl-cyclobuty1)-methanol (34.5 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclopropylmethyp-amide (11.2 mg, 10.6 %).
FIRMS (ES-) 111/Z Cala' for C29H35C12N302 H [(M+H)--): 528.2179, found:
528.2179, Example 15 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-tert-butyl benzylamide 01 0,1-1 So 410. NH
Cl M. W. 576.62 C34H39C12N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 4-tert-butylbenzylamine (48.98 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 4-tert-butyl-benzylamide (41.8 mg, 36.25 %).
HRMS ES)( mlz Calcd for C34H39C12N30 + H [(M+H)1: 576.2543. found:
576.2541.
Example 16 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl) pyrrolidine-2-carboxylic acid (3,3-dimethyl-buty1)-amide CI
410' NH
\`
Cl' 10 M. W. 514.54 C29H37C12N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 3,3-dimethylbutylamine (30.36 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) 15 at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl) pyrrolidine-2-carboxylic acid (3,3-dimethyl-buty1)-amide (30.4 mg, 29.5 %).
FIRMS (ES-') mi./ Cala r C29H37C12N30 H [(M-1-1-01: 514,2387. found: 514.2384.
20 Example 17 Preparation of rac-(2R,3R,4R,5 S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2,2-dimethyl-propy1)-amide CI H
40 \\
0, M. W. 500.52 C281135C12N30 25 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 2,2-dimethyl-propylamine (34.2 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2,2-dimethyl-propy1)-amide (24.6 mg, 24.6 %).
HRMS (ES-) nilz Caled for C28H35C12N30 + H [(11/4,1+H)1: 500.2230. found:
500.2229.
Example 18 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide H F
CI
= NH F
CI
M. W. 512.41 C25H26C12F3N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld, 2,2,2-trifluoroethylamine (29.7 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2C12 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was concentrated then purified by flash column (Si02, 1-20% of Et0Ac in Heptane) to afford rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (2,2-dimethyl-propy1)-amide (48.1 mg, 46.9 %).
HIS (ES-) mlz Caled for C25H26C12F3N30+ H [( M+H)1: 512.1478, found: 512.1478.
Example 19a Preparation of (2R,3S,45,5S)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-5-((S)-2-hydroxymethyl-pyrrolidine-1-carbony1)-pyrrolidine-3-carbonitrile CI
= NCR__ NH OH
Cl \\N
M. W. 514.494 C28H33C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with (S)-1-pyrrolidin-2-yl-methanol (30.3 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight. The mixture was then diluted with CH2C12 and washed with water, brine.
The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (30-95% of MeCN/water) to give (2R,3S,4S,5S)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-5-((S)-2-hydroxymethyl-pyrrolidine-1-carbony1)-pyrrolidine-3-carbonitrile (12.0 mg, 11.7 %).
FIRMS (ES-) rwrz Cala' for C28H33C12N302 H [(+H)-]: 514.2023, found: 514.2023.
Example 19b Preparation of (2S,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-54S)-2-hydroxymethyl-pyrrolidine-1-carbonyl) pyrrolidine-3-carbonitrile CI
Ow.
c i M. W. 514.494 C281-133C12N302 Reverse phase chromatography separation from the above example (Example 19a) gave (2S,3R,4R,5R)-4-(3-chloro-pheny1)-3-(4-chloro-pheny1)-2-(2,2-dimethyl-propyl)-5-((S)-2-hydroxymethyl-pyrrolidine-1-carbonyl) pyrrolidine-3-carbonitrile (18.1 mg, 17.6 %).
HRIVIS (ES-) 1:11/Z Calcd for C28H33C12N302 4- H [(M+H)-]: 514.2023, fund:
514.2023.
Example 20 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [2-(3,4-dimethoxy-pheny1)-ethyTmethyl-amide CI co,N 0 Cl Or' M. W. 608.606 C34H39C12N303 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol) prepared in Example ld was reacted with [2-(3,4-dimethoxy-pheny1)-ethyl]-methyl-amine (58.6 mg, 0.3 mmol), HATU (76.0 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [2-(3,4-dimethoxy-pheny1)-ethy1]-methyl-amide (57.3 mg, 48.26 %) as a white powder.
HRMS (ES-) miz Catod fir C34H39C12N303 H [(M+H)-I: 608.2441, found: 608.2437, Example 21 Preparation of rac-(2R,3R,4R,5 S)-3 -(3 -chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 2-(3,4-dimethoxy-phenyl)ethyl amide Cl N 0 44* NH 0 CI
M. W. 594.579 C33H37C12N303 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 2-(3,4-dimethoxy-phenyl)ethyl amine (30.3 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) to at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 2-(3,4-dimethoxy-phenyl)ethyl amide (53.6 mg, 45.07 %).
RMS (ES') raiz Calcd for C33H37C12N303 H 504.2285, found: 594.2283.
Example 22 Preparation of rac-(2R,3R,4R,5 S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide N CI
CI
=
NH
CI
M. W. 572.936 C30H29C13FN30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 3-chloro-2-fluoro-benzyl amine (47.9 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide (24.5 mg, 21.4 %).
HRMS (ES') MIZ Calcd for C301-129C13FN30 + 1-1 i(M+H)1: 572.1433. found:
572.1431.
Example 23a Preparation of (2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-1-hydroxymethy1-3-methyl-buty1)-amide CI
=NH
Oro' Cl M. W. 530.54 C29H37C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld, (R)-2-amino-4-methyl-pentan-1-ol (35.16 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2C12 and washed with water, brine.
The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (30-95% of MeCN/water) to give (2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-5 pyrrolidine-2-carboxylic acid ((R)-1-hydroxymethy1-3-methyl-buty1)-amide (26.2 mg, 24.7%).
HRMS (ES') 1111Z Calcd for C29H37C12N302 -4- 1-1 RM+1-1)'1: 530.2336, fbuncl:
530.2333.
Example 23b Preparation of (2S,3S,4S,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-10 propy1)-pyrrolidine-2-carboxylic acid ((R)-1-hydroxymethy1-3-methyl-buty1)-amide CI =
NH
CI \\N
M. W. 530.54 C29H37C12N302 Reverse phase chromatography separation from the above example (Example 23a) gave (2S,3S,4S,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-15 pyrrolidine-2-carboxylic acid ((R)-1-hydroxymethy1-3-methyl-buty1)-amide (23.3 mg, 21.9 %).
HRMS ES')( Calcd for C29H37C12N302 H [INI+H) 1: 530.2336. found:
530.2336.
Example 24 Preparation of rac-(2R,3R,4R,5 S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-20 dimethylpropy1)-pyrrolidine-2-carboxylic acid 3,4-difluoro-benzylamide Cl N
F
NH
Cl M. W. 556.49 C30H29C12F2N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 3, 4-difluoro-benzyl amine (42.94 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 3,4-difluoro-benzyl amide (53.5 mg, 48.1 %).
HRMS (ES') 1111Z Calcd for C30H29C12F2N30+ H [(I'4+H) I: 556.1729. found:
556.1728.
Example 25a Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Cl OH
= NH F OH
"
CI
M. W. 431.37 C23H24C12N202 .C2HF302 To a solution of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example lc (2 g, 4.12 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (10 mL).
The reaction mixture was stirred at room temperature for 18 h, and concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried under reduced pressure to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.1 g, 94%) HRMS (ES' ) III/Z Calcd for C23H24C12N202+ H [(M+14)1: 431.1288, found:
431.1287.
Example 25b Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide OH
CI
= NH
µ'µ
C1' N
M. W. 488.46 C26H31C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 25a (0.5 g, 1.1 mmol) was reacted with 3-amino-1-propanol (Aldrich) (0.4 g, 5.3 mmol), HATU (0.5 g, 1.31 mmol) and iPr2NEt (1 g, 7.7 mmol) in CH2C12 (30 mL) at room temperature for 24 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide as a white solid (0.56 g, 93%).
FIRMS (IS) m/z C.'aled for C26H31 Cl2N302 Fi [( M 11)1: 488.1866, than&
488.1864.
Example 26a Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile CI
F
N
CI
M. W. 292.14 C15H8C12FN
In a manner similar to the method described in Example lb, 4-chlorobenzyl cyanide (8.9 g, 59 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (Oakwood) (10 g, 63 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (300 mL) at 40 C for 5 h to give (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile as a white powder (16 g, 92%).
Example 26b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester c F
NH
1101 µ
CI
M. W. 505.46 C27H31C12FN202 In a manner similar to the method described in Example lc, [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile (2.3 g, 7.9 mmol) prepared in Example 26a, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in 1,2-dichloroethane (130 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2.7 g, 68%).
Example 26c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
NH
1101 uµ' CI
M. W. 449.36 C23H23C12FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 26b (0.8 g, 1.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.9 g, 100%).
FIRMS (ES-) rah Calcd for C23H23C12FN202+ H [(M-1-1-1)]: 449.1194. found:
449.1 194.
Example 26d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [2-(cis-2,6-dimethyl-morpholin-4-y1)-ethyl]-amide CI F
NH
M. W. 589.58 C31H39C12FN402 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.20 g, 0.36 mmol) was reacted with 4-(2-aminoethyl)-cis-2,6-dimethylmorpholine (Oakwood) (0.20 g, 1.2 mmol), HATU (0.3 g, 0.78 mmol) and iPr2NEt (0.60 g, 4.6 mmol) in CH2C12 (20 mL) at room temperature for 20 hrs to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [2-(cis-2,6-dimethyl-morpholin-4-y1)-ethyl]-amide as a white solid (0.20 g, 94%). HMS (ES') rniz Cale(' tbr C311-13902FN402¨ H [(M-41) ]: 589.2507, found: 589.2507, Example 27 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-cyclopropyl-ethyl)-amide H
CI
= NH
CI 1=1"' \\N
M. W. 498.50 C28H33C12N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 25a (0.16 g, 0.37 mmol) was reacted with 2-cyclopropylethylamine (Bridge Organics) (0.1 g, 1.1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2 mmol) in CH2C12 (20 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-cyclopropyl-ethyl)-amide as a white solid (0.11 g, 37%).
FIRMS (ES ') rn/z Cala for C28H33C12N30-i- H Mi IT) 'I: 498,2074, -found:
498.2075.
Example 28 Preparation of rac-(3- {[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino}-propy1)-carbamic acid tert-butyl ester H
CI 0.1,N
= NH
CI
M. W. 587.59 C311-140C12N402 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid prepared in Example 25a (1 g, 1.8 mmol) was reacted ',vith N-Boc-1,3-diaminopropane (Aldrich) (0.7 g, 4 mmol), HATU (1.4 g, 3.7 mmol) and iPr2NEt (2.8 g, 21 mmol) in CH2C12 (100 mL) at room temperature for 60 h to give rac-(3- {[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrro lidine-2-carbonyl] -amino } -propy1)-carbamic acid tert-butyl ester as a white solid (0.92 g, 87%).
R MS (ES )M' led for C311-140C12N402 H [(NI F I) j: 587.2550, 587.2551.
Example 29 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-amino-propy1)-amide NH
CI
= NH
CI
5 M. W. 487.47 C26H32C12N40 To a solution of rac-(3-{[(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester prepared in Example 28 (0.9 g, 1.5 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 h, and concentrated. The 10 residue was then neutralized with saturated aqueous NaHCO3 solution, and then extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, concentrated, dried under reduced pressure to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-amino-propy1)-amide as a white solid (0.8 g, 100%) 15 FIRMS (ES) mjz Caled ibr C26H32C12N40 H [( M 11)1: 487.2026. found:
487.2027.
Example 30 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [3-(1-acetyl-piperidin-4-ylamino)-propyl]-amide CI H ,iNsCN_O
= NH
AO' Cl M. W. 640.65 C34H43C12N503 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propy1)-amide prepared in Example 29 (0.18 g, 0.37 mmol) was reacted with 1-acetylpiperidine-4-carboxylic acid (Lancaster) (0.7 g, 0.58 mmol), HATU (0.3 g, 0.78 mmol) and iPr2NEt (0.5 g, 3.9 mmol) in CH2C12 (20 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1-acetyl-piperidin-4-ylamino)-propyll-amide as a white solid (0.16g, 67%).
FIRMS (ES-) rntz Calcd for C34H43C12N5034- H [(M+H)-]: 640.2816, found:
640.2818.
Example 31a Preparation of intermediate [3-Methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester 00y M. W. 199.16 C11H21NO2 In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with isovatera Welly& (Alfa) (0.43 g, 5 nunoi) in CH2C12 at room temperature for 18 h to give [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.98 g, 98%).
Example 31b Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester = Ncl H
40 \\
M. W. 473.45 C26H3002N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 31a (2 g, 10 mmol) was reacted with (Z)-3-(3-chloro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile (2 g, 7.3 mmol) prepared in Example lb, AgF
(1.3 g, 10 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.7 g, 20%).
Example 31c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI
= NH
F.)EÇOH
Cl .1"µµ µN
M. W. 417.34 C22H22C12N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 31b (0.4 g, 0.85 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.4 g, 89%).
HRMS (ES') miz Caled fbr C22H22C12N202-i- H 101+H11: 417.1 1131, found: 417.1 131.
Example 31c1 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide H OH
Cl Csb NH*':C.C.4.)-1' ""
M. W. 474.43 C25H29C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 31c (0.6 g, 1.1 mmol) was reacted with 3-amino-1-propanol (Aldrich) (0.4 g, 5.3 mmol), HATU and iPr2NEt in CH2C12 at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide as a white solid (0.21 g, 40%).
HR MS (ES') Mk Ca icd for C25H29C12N302 t 1111 (II)]: 474. 1'710, found :
474,1 710.
Example 32a Preparation of intermediate {[1-(3-Chloro-pheny1)-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester IN
CI
M. W. 253.73 C13H16CN02 In a manner similar to the method described in Example la, glycine tert-butyl ester (1.31 g, 10 mmol) was reacted with 3-chlorobenzaldehyde (Aldrich) (1.4 g, 10 nwhol) in CH2C12 at room temperature for 18 h to give {[1-(3-chloro-phenyl)-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester as a plae yellow oil (2.4 g, 95%).
Example 32b Preparation of intermediate (Z)-2-(4-chloro-phenyl)-5,5-dimethyl-hex-2-enenitrile 1.1 M. W. 233.74 C14H16C1N
In a manner similar to the method described in Example lb, 4-chlorobenzyl cyanide (4.5 g, 30 mmol) was reacted with 3,3-dimethyl-butyraldehyde (Aldrich) (3 g, 30 mmol), methanolic solution (25 wt%)of sodium methoxide (7 mL, 30 mmol) in methanol (130 mL) at room temperature for 3 h to give (Z)-2-(4-chloro-phenyl)-5,5-dimethyl-hex-2-enenitrile as a colorless oil (5 g, 71%).
Example 32c Preparation of intermediate rac-(2R,3R,4R,5S)-5-(3-Chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-3-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester OfC)?( NH
C
CI I
M. W. 487.47 C27H32C12N202 In a manner similar to the method described in Example lc, {[1-(3-chloro-pheny1)-meth-(E)-ylidene]-aminol-acetic acid tert-butyl ester prepared in Example 32a (2.6 g, 11 mmol) was reacted with (Z)-2-(4-chloro-phenyl)-5,5-dimethyl-hex-2-enenitrile (2 g, 7.9 mmol) prepared in Example 32b, AgF (1.3 g, 10 mmol), and triethylamine (2.2 g, 22 mmol) in 1,2-dichloroethane (100 mL) at room temperature for 24 h to give rac-(2R,3R,4R,5S)-5-(3-Chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-3-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 31%).
HRMS (ES') rulz Cato(' for C27H32C12N202-'- H1(I4+11)' I: 487.1914, found:
487.1912.
Example 32d Preparation of intermediate rac-(2R,3R,4R,5S)-5-(3-Chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-3-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid of0H
NH
10' 110 c, FOH
F¨Ao CI
M. W. 431.37 C23H24C12N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-5-(3-Chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 32c (1.2 g, 2.5 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-5-(3-Chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyfl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (1.0 g, 76%).
HIRS (ES ) miz Ca la! for C23H24C12N202+ i1 [(N1-HI-1) ]: 431.1288, found: 431 1288.
Example 32e Preparation of rac-(2R,3R,4R,5R)-5-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-3-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide OH
CI
CI N
M. W. 488.46 C26H31C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5R)-5-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 32d (0.6 g, 1.1 mmol) was reacted with 3-amino-1-propanol (Aldrich) (0.6 g, 8 mmol), HATU and iPr2NEt in CH2C12 at room temperature to give rac-(2R,3R,4R,5R)-5-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide as a yellow solid (0.12 g, 22%).
HRMS (ES') III/Z Calcd for C26H31 Cl2N3 02-1- H [(M+H) I: 488.1866, found:
488.1864.
Example 33a Preparation of intermediate (S)-2-[3,3-Dimethyl-but-(E)-ylideneamino]-propionic acid tert-butyl ester AN
\/*<
5 M. W. 227.35 C13H25NO2 A mixture of L-alanine tert-butyl ester hydrochloride (Bachem) (1.8 g, 10 mmol) and MgSO4 in CH2C12 (100 mL) was added triethylamine (1.5 g, 15 mmol). The mixture was stirred at room temperature for 1 h, and 3,3-dimethyl-butyraldehyde (1 g, 10 mmol) was added.
The reaction mixture was stirred at room temperature for 18 h. The mixture was filtered, and the filtrate was 10 washed with water, brine, and concentrated. The residue was dried under reduced pressure to give (S)-2-[3,3-dimethyl-but-(E)-ylideneamino]-propionic acid tert-butyl ester as colorless oil (2,3 g, 100%) which was used without further purification.
Example 33b 15 Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-Chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-2-methyl-pyrrolidine-2-carboxylic acid tert-butyl ester CI (:).0?( 0, M. W. 501.50 C28H34C12N202 In a manner similar to the method described in Example lc, (S)-2-[3,3-dimethyl-but-(E)-20 ylideneamino]-propionic acid tert-butyl ester prepared in Example 33a (2.4 g, 11 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (2.4 g, 8.8 mmol) prepared in Example lb, AgF (1.6 g, 13 mmol), and triethylamine (2.4 g, 24 mmol) in 1,2-dichloroethane (150 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-Chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic 25 acid tert-butyl ester as a white foam (2.4 g, 54%).
FIRMS (ES') mlz Cala for C28H34C121\1202-1- 11 [1M 50i .2070, found:
501.2066.
Example 33c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-2-methyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid cl of0H
= NH FLOH
CI NµN
M. W. 445.39 C24H26a2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 33b (1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-2-methyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.1 g, 98%).
R. MS (ES') ni/z. Coiled for C24H26C12N202 1 1 [(M-F1-1)']: 445.1444, found:
445.1443.
Example 33d Preparation of rac-(2R,3R,4R,5 S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-2-methyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide OH
CI
= NH
N.\
CID"' M. W. 502.48 C27H33C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,55)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 33c (0.4 g, 0.7 mmol) was reacted with 3-amino-1-propanol (Aldrich) (0.4 g, 5.3 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (1 g, 7.7 mmol) in CH2C12 (30 mL) at room temperature for 24 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-2-methyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propy1)-amide as a white solid (0.21 g, 60%).
HRMS (ES') 1:111Z Calcd for C27H33C12N302-4- 1-1 [(,14-1-1)'1: 502.2023, found: 502.2021.
Example 34a Preparation of intermediate [2-Cyclopentyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester OO
IUD
M. W. 225.33 C13H23NO2 In a manner similar to the method described in Example la, glycine tert-butyl ester (0.7 g, 5 mmol) was reacted with 2-cyclopentylacetaidehyde Bctaphartna) (0.9 g. 8 mmol) in CH2C12 at room temperature for 20 h to give [2-cyclopentyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1 g, 90%).
Example 34b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid tert-butyl ester CI F
= 1\1111-1 0,...
CI
M. W. 517.48 C281-I31C12FN202 In a manner similar to the method described in Example lc, [2-cyclopentyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 34a (1 g, 4.4 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile (0.9 g, 3 mmol) prepared in Example 26a, AgF (1.3 g, 10 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (150 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid tert-butyl ester as a white foam (0.4 g, 26%).
Example 34c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid trifluoroacetic acid CI F orOH
= NH F OH
10 ' \'µ
Cl M. W. 461.37 C24H23C12FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid tert-butyl ester prepared in Example 34b (0.4 g, 0.77 mmol) was reacted ,vvith trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid trifluoroacetic acid as a off white solid (0.5 g, 100%).
Example 34d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide NH OH
I.1"" =
CI
M. W. 548.48 C281-13202FN303 In a manner similar to the method described in Example 3b, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid trifluoroacetic acid prepared in Example 34c (0.4 g, 0.71 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.2 g, 1.4 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (0.6 g, 4.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.14 g, 36%).
FIRMS (ES') rd/z Ca for C28H32C12FN303 H [( WI: 548,1878, found:
548.1880.
Example 35 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide CI F 0(1\5<" OH
= NH
CI
M. W. 520.47 C27H32C12FN302 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.2 g, 0.36 mmol) was reacted with 2-amino-2-methyl-1-propanol (Fluka) (0.2 g, 2.2mmol), HATU (0.3 g, 0.78 mmol) and iPr2NEt (0.5 g, 3.8 mmol) in CH2C12 (10 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide as a white solid (0.17 g, 91%).
EIRMS (ES-) mlz Cated for C27H3202FN302+ H M+/-01: 520.1929, found: 590.1929.
Example 36 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-hydroxy-2,2-dimethyl-propy1)-amide OH
CI F
= NH
CI
M. W. 534.5 C28H34C12FN302 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.2 g, 0.36 mmol) was reacted with 3-amino-2,2-dimethyl-1-propanol (TCI-US) (0.2 g, 2 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.2 g, 1.6 mmol) in CH2C12 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-2,2-dimethyl-propy1)-amide as a white solid (0.16 g, 83%).
EIRMS (ES-) mh Ca led for C28H34C12FN302+ H [( M-1-1-01: 534.2085, found:
534.2084.
Example 37 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide OH
CI F
= NH
110ClN
""
M. W. 536.47 C27H32C12FN303 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.3 g, 0.54 mmol) was reacted with 2-(2-aminoethyl)ethanol (Aldrich) (0.15 g, 1.4 mmol), HATU (0.3 g, 0.75 mmol) and iPr2NEt (0.6 g, 5 4.8 mmol) in CH2C12 (20 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide as a white solid (0.18 g, 62%).
HRMS (ES-) miz Caled for C27H32C12FN303+ H M+FOI: 536.1878, found: 536.1877.
10 Example 38 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-acetylamino-ethyl)-amide CI F
= NH
CI .
M. W. 533.47 C27H31C12FN402 15 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.3 g, 0.54 mmol) was reacted with N-acetylethylenediamine (Aldrich) (0.15 g, 1.5 mmol), HATU (0.3 g, 0.75 mmol) and iPr2NEt (0.6 g, 4.8 mmol) in CH2C12 (20 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-20 chloro-2-fluoro-pheny1)-4-(4-chloro-pheny0-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-acetylamino-ethyl)-amide as a white solid (0.24 g, 83%).
HR JS (FS') m/z Calcd ft-if C27H3102FN402 [t M-1 1-01: 533,1881, found:
533.1882.
Example 39 25 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (3-imidazo1-1-yl-propy1)-amide eNN
CI F N
NH
CI
M. W. 556.51 C29H32C12FN50 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.2 g, 0.36 mmol) was reacted with 1-(3-aminopropopyl)imidazole (Aldrich) (0.15 g, 1.2 mmol), HATU (0.3 g, 0.75 mmol) and iPr2NEt (0.5 g, 3.6 mmol) in CH2C12 (20 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-imidazol-1-yl-propy1)-amide as a white solid (0.19 g, 94%).
HMIS (ES') nblz Cala C29H32C12FN50 1 11 1( M11101: 556.2041. found:
556.2040.
Example 40 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-4-hydroxy-3-methyl-buty1)-amide CI F
= NH
0%." 4%µ, CI
M. W. 534.5 C28H34C12FN302 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.16 g, 0.29 mmol) was reacted with (R)-4-amino-2-methyl-1-butanol (TCI-US) (0.1 g, 1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2 mmol) in CH2C12 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-4-hydroxy-3-methyl-butyl)-amide as a white solid (0.1 g, 65%).
HRMS (ES') mlz Caled for C28H34C12FN302+ H [(M+11)'1: 534.2085, found:
534.208.4.
Example 41 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid cyclopropylmethoxy-amide CI F
= NH
CI
M. W. 518.46 C27H30C12FN302 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.15 g, 0.27 mmol) was reacted with O-S cyclopropylmethylhydroxyamine (HUHU Tech) (0.1 g, 1.1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2 mmol) in CH2C12 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid cyclopropylmethoxy-amide as a white solid (30 mg, 21%).
IIRMS (ES') miz Cala ibt= C27H30C12FN3024- ri [(M fl]: 518.1772, found:
518.1773, Example 42a Preparation of intermediate rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester CI 0/.02( = NH
CI \\ 1101 CI
M. W. 527.88 C28H25C13N202 In a manner similar to the method described in Example lc, 41-(3-Chloro-pheny1)-meth-(E)-ylidene]-aminol-acetic acid tert-butyl ester prepared in Example 32a (2 g, 7.6 mmol) was reacted with (Z)-3-(3-chloro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile (0.55 g, 2 mmol) prepared in Example lb, AgF (1.3 g, 10 mmol), and triethylamine (1.9 g, 19 mmol) in dichloromethane (30 mL) at 50 C for 20 h to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.45 g, 44%).
HRMS (ES-) miz Calcd, for C28H25C13N202 H [(1\4+H)-1: 527.1055, found:
527.1051.
Example 42b Preparation of intermediate rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI of0H
NH
"
M. W. 471.77 C24H17C13N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 42a (0.45 g, 0.85 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.49 g, 98%).
HRMS (ES') Tri1.7. Ca led for C24H17C13N202+ H [(N1 j: 471.0429, found:
471,0429.
Example 42c Preparation of rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide NH IC+
C
CI
M. W. 598.96 C31F13003N303 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 42b (0.3 g, 0.5 mmol) was reHcted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.3 g, 2 mmol), HATU (0.3 g, 0.75 mmol) and iPr2NEt (0.6 g, 4 mmol) in CH2C12 (30 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl]-amide as a off white solid (0.25 g, 83%).
HRMS (ES +) rniz Calcd for C31F130C13N303 H [(M+H)+]: 598.1428, found:
598.1424.
Example 42d Preparation of rac-(2R,3R,4R,5 S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Cl OH
CI
NH
CI
µµ I101 M. W. 558.89 C28H26C13N303 To a solution of rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 42c (0.4 g, 0.66 mol) in tetrahydrofuran (10 mL) was added aqueous HC1 solution (1N, mL). The reaction mixture was stirred at room temperature for 2 h, then concentrated. Then the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, aqueous saturated NaHCO3, brine, dried over MgSO4, concentrated, dried 5 under reduced pressure to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyp-amide as a white solid (0.2 g, 89%).
HRMS (ES-) mlz Cated for C281-12603N303-, H [(M+H 11: 558.1113, found: 558. 11 10.
10 Example 43a Preparation of intermediate [2-ethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester oY
M. W. 213.32 C12H231\102 In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted i 2-et hylbta yra Idell2yrde (Aldrich) (0.55 g, 5 mmo11 in CH2C12 at room temperature for 18 h to give [2-ethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1 g, 94%).
Example 43b Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI orOK
NH
110"µµ \.%
CI
M. W. 487.5 C27H32C12N202 In a manner similar to the method described in Example lc, [2-ethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 43a (1 g, 4.7 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.91 g, 3.3 mmol) prepared in Example lb, AgF (1.5 g, 12 mmol), and triethylamine (1.9 g, 19 mmol) in 1,2-dichloroethane (50 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 68%).
Example 43c 5 Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid = NH FLOH
C I
M. W. 431.37 C23H24C12N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-10 phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 43b (1.1 g, 2.3 mmol) was reacted v.iiiitrifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.2 g, 98%).
15 HRMS ES)( mitz Calcd for C23H24C12N202 [(M+H) `I: 431.1288, found: 431.1286.
Example 43d Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI
NH OH
1101 P'µ
CI
M. W. 518.48 C27H33C12N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 43c (0.55 g, 1 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.2 g, 1.3 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (0.2 g, 1.5 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.5 g, 96%).
H[RMS (ES-) ralz Calcd for C27H33C12N3034- H M+1-1)1: 518.19727 found:
518.1970.
Example 44a Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide OH
NH
CI
M. W. 536.47 C27H32C12FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.25g, 0.44 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.2 g, 1.3 mmol), HATU (0.3 g, 0.79 mmol) and iPr2NEt (0.5 g, 3.9 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21g, 89%).
HR MS (ES ) Trilz Ca tcd for C27H32C12FN303 H 536,1 878, found: 536.1875.
Example 44b Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
OH"
NH
CI
M. W. 536.47 C27H32C12FN303 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.19 g) was separated by chiral SFC chromatography to provide chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (85 mg, 45%) and chiral-(2S,3R,4SR,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (81 mg, 43%).
Example 45 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
NH OH
CI
M. W. 504.46 C26H31C12N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 31c (0.4 g, 0.75 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.25 g, 1.6 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (1 g, 7.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.4 g, 95%).
HRMS (ES') MIZ Calcd for C26H31 Cl2N3 03-1- H [(M-41)' ]: 504.1815, found:
50.4.1815.
Example 46a Preparation of intermediate rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester CI ofiCy 40' \\
CI
M. W. 473.45 C26H30C12N202 In the preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester as described in Example 31b, rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester was obtained as the second product: white powder, Yield: 0.82 g, 24%.
HR1V1S (ES) Calcd for C26H30C12N202 H [0,4+H)]: 473.1757. found:
,173.1756.
Example 46b Preparation of intermediate rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI
NH F..".F.õOH
õõ
\\
CI
M. W. 417.34 C22H22C12N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 46a (0.6 g, 1.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.6 g, 89%).
Example 46c Preparation of rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
= 0 OH
NH
*kw CI
M. W. 504.46 C26H31C12N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 46b (0.6 g, 1.1 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.3 g, 2 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (1.2 g, 9.3 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HO
solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.6 g, 95%).
FIRMS (ES-) raiz Calcd for C26H31C12N303-1.- H [(1+H)1: 504.1815, found:
504.18 I 6.
Example 47a Preparation of intermediate rac-(2R,3MR,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester CI ic,(0?( NH
CI 1.1 C
M. W. 487.5 C27H3202N202 In the preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as described in Example 43b, rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester was obtained as the second product: white foam, Yield, 0.26 g, 16%.
Example 47b Preparation of intermediate rac-(2R,3R4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI of.OH
NH FOH
W
CI =c F
M. W. 431.37 C23H24C12N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 47a (0.25 g, 0.5 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.2 g, 73%).
f-1RMS (ES) T1VZ Ca la! for C23H24C12N202+ ]: 431.1288, found: 431 .1285.
Example 47c Preparation of rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI
OH
= NH
CI \\N
r 5 M. W. 518.48 C27H33C12N303 In a manner similar to the method described in Example 42e, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 47b (0.27 g, 0.5 mmol) was routed with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.2 g, 1.3 mmol), HATU (0.4 g, 1.1 mmol) and 10 iPr2NEt (0.4 g, 3 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.23 g, 88%).
FIRMS (ES ') ITI/Zlod for C27H33C12N303+ H kM+H)1: 518.19725 found: 518.1971.
Example 48a Preparation of intermediate (1-ethyl-propylideneamino)-acetic acid tert-butyl ester M. W. 199.16 C111-121NO2 A mixture of glycine tert-butyl ester (Alfa) (0.66 g, 10 mmol) and 3-pentanone (6 g, 70 mmol) in ethanol (6 mL) was heated at 110 C in a sealed tube for 48 h. The reaction mixture was concentrated and dried in vacu to give crude (1-ethyl-propylideneamino)-acetic acid tert-butyl ester as a colorless oil (1.0 g). The crude product contains unreacted glycine tert-butyl ester and was used without further purification.
Example 48b Preparation of intermediate rac-(2R,3MR)-3-(3-chloro-pheny1)-4-(4-ehloro-pheny1)-4-eyano-5,5-diethyl-pyrrolidine-2-carboxylic acid tert-butyl ester CI
NH
CI
M. W. 473.45 C26H30a2N202 In a manner similar to the method described in Example lc, crude (1-ethyl-propylideneamino)-acetic acid tert-butyl ester prepared in Example 48a (1.2 g, 6 mmol) was roacted with (Z)-3-(3-chloro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile (0.7 g, 2.5 mmol) prepared in Example lb, AgF (1.9 g, 15 mmol), and triethylamine (2.5 g, 25 mmol) in 1,2-dichloroethane (130 mL) at room temperature for 10 h to give rac-(2R,3R,4R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-eyano-5,5-diethyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a yellow gum (0.33 g, 28%).
Example 48c Preparation of intermediate rac-(2R,3R4R)-3-(3-chloro-pheny1)-4-(4-ehloro-pheny1)-4-eyano-5,5-diethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI
= NH
FÇOH
CI 11 11"µ \\I\I
M. W. 417.34 C22H22C12N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 48c (0.33 g, 0.7 mmol) was reacted \ivith trifluoroacetie acid in dichloromethane at room temperature to give rac-(2R,3R,4R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid trifluoroacetie acid as a off white foam (0.35 g, 96%).
FIRMS (ES-) mlz Caied for C22H22C12N202+ H )-I: 417.1 13 1.0429, found:
417,1132.
Example 48d Preparation of rac-(2R,3R,4R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Cl OH
= NH
µ
CI
M. W. 504.46 C26H31C12N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 48c (0.33 g, 0.62 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1 mmol), HATU (0.34 g, 0.89 mmol) and iPr2NEt (1 g, 7.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a off white solid (0.4 g, 95%).
FIRMS (ES') m/z Calcd for C26H31 Cl2N303 H [(MHI)']: 504.1815, found:
50,1.1815.
Example 49a Preparation of intermediate [2-methyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester 0:200y-M. W. 185.27 C10H19NO2 In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with isobutyraldehyde (Aldrich) (OA g, 5 rnmol) in CH2C12 at room temperature for 20 h to give [2-methyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.9 g, 97%).
Example 49b Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid tert-butyl ester CI
NH
101"' CI
M. W. 459.42 C25H28C12N202 In a manner similar to the method described in Example lc, [2-methyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 49a (1 g, 5.4 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.85 g, 3.1 mmol) prepared in Example lb, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.64 g, 45%).
Example 49c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI c;,e0H
= NH
F..EÇOH
[110 .%µ
CI
M. W. 403.31 C21ii20C12N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 49b (0.64 g, 1.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.7 g, 100%).
FIRMS (ES) rit/z Calcd for C211420C12N202-+ H [( M IN: 403.0975, found:
403.0974.
Example 49d Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
=
NH OH
101 \'µ
CI
M. W. 490.43 C25H29C12N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 49c (0.5 g, 0.97 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.25 g, 1.7 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (1 g, 7.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.25 g, 52%).
HMIS (ES) rmiz Calcd fbr C25H29C12N303 t H [(Mi I {)]: 490.1659, found:
490.1657.
Example 50a Preparation of intermediate {[1-cyclohexyl-meth-(E)-ylidene]-aminol-acetic acid tert-butyl ester M. W. 225.33 C13H231\102 In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with cyclohexallecurbalcichyde (Aldrich) (0,6 g, 5 mmol) in CH2C12 at room temperature for 20 h to give {[1-cyclohexyl-meth-(E)-ylidene]-aminol-acetic acid tert-butyl ester as a colorless oil (1.2 g, 100%).
Example 50b Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid tert-butyl ester CI c;,C7( NH
.1" \\
M. W. 499.49 C28H3202N202 In a manner similar to the method described in Example lc, {[1-cyclohexyl-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester prepared in Example 50a (1.2 g, 5.3 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (1 g, 3.7 mmol) prepared in Example lb, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.69 g, 38%).
5 Example 50c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI
= NH
µµ
CI N =
M. W. 443.38 C24H24C12N202.C2HF302 10 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 50b (0.69 g, 1.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off 15 white solid (0.8 g, 100%).
HRMS (ES) raiz Calcd {by C24H24C12N202-t H [(M IN: 443,1288, found: 443.1286.
Example 50d Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
= NH OH
110 \µ
M. W. 530.49 C28H33C12N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 50c (0.5 g, 0.76 mmol) was reacted with 2-((S)-2,2-25 dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.3 g, 2 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (0.9 g, 7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.25 g, 62%).
FIRMS (ES-) fillz Caled for C28H33C12N3034- H kM+H)--1: 530.1972, found:
530.197 Example 51a Preparation of intermediate [2,2-dimethyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester M. W. 199.16 C11H21NO2 In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with triincillytacetaldettyde (Aldrich) (0.42 g, 5 ltitnot) in CH2C12 at room temperature for 20 h to give [2,2-dimethyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.0 g, 100%).
Example 51b Preparation of intermediate rac-(2R,3S,4R,5S)-5-tert-buty1-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester Cl F oe0?c/
CI
M. W. 491.44 C26H29C12FN202 In a manner similar to the method described in Example lc, [2,2-dimethyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 51a (1 g, 5 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile (0.8 g, 2.7 mmol) prepared in Example 26a, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (50 mL) at room temperature for 24 h to give (2R,3S,4R,5S)-5-tert-Buty1-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.4 g, 30%).
Example 51c Preparation of intermediate rac-(2R,3S,4R,5S)-5-tert-buty1-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
= N FFOH
1(!) CI [1101" \\N
M. W. 435.33 C22H21 C12FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-tert-Buty1-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 51b (0.3 g, 0.6 mmol) was reactd with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-tert-Buty1-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.4 g, 100%).
FIRMS (ES') iniz (Ailed for C22H21C12FN202-F- 1-1 [(NI -F-H)']: 435.1037, found: 435.1036, Example 51d Preparation of rac-(2R,3S,4R,5S)-5-tert-buty1-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F OH
OH
= NH
NN, CI
M. W. 522.45 C26H30C12FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 51c (0.4 g, 0.73 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.2 g, 1.3 mmol), HATU (0.3 g, 0.79 mmol) and iPr2NEt (0.6 g, 4.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-tert-buty1-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.22 g, 58%).
FIRMS (ES ni/z Calcd for C26H30C12FN303 l [(NI 1 l 22.1721; found:
522.1719, Example 52a Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile CI
F
CI
M. W. 310.13 C15H7C12F2N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (5 g, 30 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5 g, 32 mmol), methanolic solution (25 wt%) of sodium methoxide (21 mL, 92 mmol) in methanol (200 mL) at 45 C for 5 h to give (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile as a white powder (9 g, 97%).
Example 52b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F c,(0?(' NH
Cl F N
M. W. 523.46 C27H30C12 F2N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.3 g, 11 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (2.5g, 8 mmol) prepared in Example 52a, AgF (0.7 g, 5.5 mmol), and triethylamine (2.9 g, 29 mmol) in dichloromethane (200 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (3 g, 64%).
Example 52c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F of0H
= NH
CI FN
M. W. 467.35 C23H2202P2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 52b (0.4 g, 0.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.5 g, 100%).
FIRMS (ES) rniz Caled for C23H22C12F2N202+ j: 467.1099, fbund: 467.1098.
Example 52d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
AO'NH OH
=N\
CI
M. W. 554.46 C27H31C12F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.4 g, 0.69 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.25 g, 1.7 mmo1), HATU
(0.35 g, 0.92 mmol) and iPr2NEt (0.75 g, 5.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.26 g, 84%).
HRMS (ES-) mlz Cated for C27H31 Cl2F2N303-,- H[( M+14)]: 554.1784, found:
554.1783.
Example 52e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F n *NH OH
Cl 5 M. W. 554.46 C27I-131C12F2N303 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.3g) was separated by chiral SFC chromatography to provide chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-10 pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (120 mg, 40%) and chiral-(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (121 mg, 40%).
15 Example 53a Preparation of intermediate rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F0 Ox, \\
CI F N
M. W. 523.46 C27H30C12F2N202 20 In preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as described in Example 52b, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester was obtained as the second product: a white foam (0.98 g, 21%).
Example 53b Preparation of intermediate rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Cl F0 OH
'410' NH
F. 11 AO
CI F -M. W. 467.35 C23H2202P2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2S,3S,4R,SS)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 53a (0.4 g, 0.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3S,4R,5S)-3-(3-Chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.5 g, 100%).
FIRMS (ES) miz Caled for C23H22C12F2N202+i1RNI-F I-1) j: 467.1099, fbund:
467.1099, Example 53c Preparation of rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide OH
NH
CI
M. W. 554.46 C27H31C12F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2S,3S,4R,5S)-3-(3-Chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 53b (0.3 g, 0.5 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1 mmol), HATU
(0.3 g, 0.79 mmol) and iPr2NEt (0.4 g, 3.1 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.26 g, 94%).
HIS (ES-) mlz Calcd for C27H31 Cl2F2N303-,- H[( M+14)]: 554,1784, found:
554.1782.
Example 54a Preparation of intermediate (Z)-2-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-pheny1)-acrylonitrile CI
F
Br M. W. 336.59 C151-1813rC1FN
In a manner similar to the method described in Example lb, 4-bromophenylacetonitrile (Aldrich) (4.5 g, 23 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5.2 g, 33 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (150 mL) at 50 C for 3 h to give (Z)-2-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-acrylonitrile as a white powder (7.8 g, 100%).
Example 54b Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-bromo-pheny1)-3-(3-ehloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F O
=NH
B
r M. W. 549.92 C27H31BrCIFN202 In a manner similar to the method described in Example lc, [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (1.1 g, 5 mmol) was reactod with (Z)-2-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-pheny1)-acrylonitrile (1.2 g, 3.6 mmol) prepared in Example 54a, AgF (1.3 g, 10 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 3 h to give rae-(2R,3S,4R,5S)-4-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 56%).
Example 54c Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F of0H
NH F-./....õOH
"
Br *IP \\NI
M. W. 493.81 C23H23BrC1FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-4-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 54b (1.1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (1.2 g, 99%).
FIRMS (ES-) ryitz Calcd for C23H23BrC1FN202¨ H Riv4-i+1)1: 493.0688; found:
493.0689.
Example 54d Preparation of rac-(2R,3S,4R,5S)-4-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide OH
NH
Br M. W. 580.92 C27H32BrC1FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,35,4R,55)-4-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 54c (0.3 g, 0.49 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1 mmol), HATU
(0.23 g, 0.6 mmol) and iPr2NEt (0.4 g, 3.1 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-4-(4-bromo-pheny1)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.18 g, 63%).
IIR NIS (ES ) /1117. Ca tat for C27H32BrC1FN303-- H [(M-1- FM: 580.1373, found: 580.1372 Example 55a Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-fluoro-pheny1)-acrylonitrile CI
F.
M. W. 275.69 C15I-I8C1F2N
In a manner similar to the method described in Example lb, 4-fluorophenylacetonitrile (Aldrich) (3.5 g, 26 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5.3 g, 34 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (200 mL) at 50 C for 3 h to give (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-fluoro-pheny1)-acrylonitrile as a white powder (5.7 g, 80%).
Example 55b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-4-(4-fluoro-pheny1)-pyrrolidine-2-carboxylic acid tert-butyl ester Ci F 0.07( 1101""
M. W. 489.01 C27H31C1F2N202 In a manner similar to the method described in Example lc, [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (1.1 g, 5 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-fluoro-pheny1)-acrylonitrile (1.25 g, 4.5 mmol) prepared in Example 55a, AgF (1.6 g, 13 mmol), and triethylamine (1.6 g, 16 mmol) in dichloromethane (100 mL) at room temperature for 5 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.6 g, 72%).
Example 55c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-4-(4-fluoro-pheny1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
"'µ FtÇOH
oi0H
41' NH
w \'µ
5 M. W. 432.90 C23H23C1F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 55b (1.6 g, 3.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-10 phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.7 g, 94%).
Example 55d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5 -(2,2-dimethyl-15 propy1)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH OH
M. W. 520.02 C27H32C1F2N303 In a manner similar to the method described in Example 42e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic 20 acid trifluoroacetic acid prepared in Example 55c (0.4 g, 0.73 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.2 g, 1.4 mmol), HATU (0.3 g, 0.8 mmol) and iPr2NEt (0.6 g, 4.6 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-4-(4-fluoro-phenyl)-pyrrolidine-2-25 carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 55%).
FIRMS (ES ') rn/z Cated for C27H32C1F2N303-t- H [(M+H ) ]: 520.2173. found:
520.2 I 75.
Example 56a Preparation of intermediate (Z)-3-(3-Chloro-2-fluoro-pheny1)-2-(2,4-dichloro-pheny1)-acrylonitrile CI
F
CI
CI
M. W. 326.59 C15H7C13FN
In a manner similar to the method described in Example lb, 2, 4-dichlorobenzyl cyanide (6 g, 32 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (6 g, 38 mmol), methanolic solution (25 wt%) of sodium methoxide (30 mL, 131 mmol) in methanol (200 mL) at 50 C
for 3 h to give (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(2,4-dichloro-pheny1)-acrylonitrile as a white powder (7 g, 67%).
Example 56b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F c3,(0.-2( = NI tH
IS
CI CI N
M. W. 539.91 C27H30C13FN202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(2,4-dichloro-pheny1)-acrylonitrile (2.2 g, 6.7 mmol) prepared in Example 56a, AgF (2 g, 16 mmol), and triethylamine (5 g, 50 mmol) in dichloromethane (200 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2.4 g, 66%).
Example 56c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F (DeOH
= NH FOH
CI OIN
M. W. 483.80 C23H22C13FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 56b (2.4 g, 7.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.7 g, 100%).
Example 56d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
=
NH OH
CI CI
M. W. 570.92 C27H3103FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 56c (0.6 g, 1 mmol) was reacted with 24(S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.3 g, 2 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (0.9 g, 7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.5 g, 88%).
FIRMS (ES ') iablz Calcd tbr C27H31C13FN303 Fi 1(M -FM' -1: 570.1488, round:
570.107, Example 56e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH OH
CI *PC' I \µI\I
M. W. 570.92 C27H31C13FN303 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.5 g) was separated by chiral SFC chromatography to provide chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (200 mg, 40%) and chiral-(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-cyano-4-(2,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (220 mg, 44%).
Example 57a Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-methyl-pheny1)-acrylonitrile CI
F
CI N
M. W. 306.17 C16H10C12FN
Step A.
A mixture of 4-chloro-2-methylbenzyl alcohol (Aldrich) (5 g, 32 mmol) in thionyl chloride (20 mL) was heated at refluxing (100 C) for 30 min. The mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous NaHCO3 solution, water, brine, dried over MgSO4, and concentrated to give 4-chloro-2-methylbenzyl chloride as a light yellow oil (5.2 g, 93%).
Step B.
To a solution of 4-chloro-2-methylbenzyl chloride (5.2 g, 30 mmol) in ethanol (40 mL) was added an aqueous solution (30 mL) of KCN (5 g, 77 mmol) at room temperature.
The reaction mixture was then heated at 100 C for 2 h. The mixture was cooled to room temperarure and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;10, then 1:4) to give 4-chloro-2-methylbenzyl cyanide as a yellow oil (3.5 g, 66%).
Step C
In a manner similar to the method described in Example lb, 4-chloro-2-methylbenzyl cyanide (3.5 g, 21 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5 g, 32 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (100 mL) at 50 C for 5 h to give (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-methyl-pheny1)-aerylonitrile as a white powder (4 g, 62%).
Example 57h Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny0-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F c3,(0.-2( = NI tH
CI 1101 \\N
M. W. 519.49 C28H33C12FN202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-methyl-pheny1)-acrylonitrile (2.3 g, 7.5 mmol) prepared in Example 57a, AgF (1.3 g, 10 mmol), and triethylamine (2.8 g, 28 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.9 g, 49%).
Example 57c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
= NH FJOH
"
CI
M. W. 463.38 C24H25C12FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 57b (1.9 g, 3.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.1 g, 98%).
Example 57d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI FOH
OH
= NH
oro CI
M. W. 550.50 C281134C12FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 57c (0.4 g, 0.69 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.2 g, 1.4 mmol), HATU
(0.4 g, 1.1 mmol) and iPr2NEt (0.8 g, 6.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.29 g, 76%).
HRMS ES)( Calcd for C28H34C12FN303+ H [0,1+11)' I: 550.2034, found:
550.2036, Example 58a Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-methoxy-pheny1)-acrylonitrile CI
CI
M. W. 322.17 C16H10C12FN0 Step A.
In a manner similar to the method described in Example 57 Step A, 4-chloro-2-methoxybenzyl alcohol (Aldrich) (4.9 g, 28 mmol) was reacted with thionyl chloride (20 mL) to give 4-chloro-2-methoxybenzyl chloride as a white solid (5.1 g, 95%).
Step B
In a manner similar to the method described in Example 57 Step B, 4-chloro-2-methoxybenzyl chloride (5.1 g, 27 mmol) was reacted with NaCN (3 g, 61 mmol) in ethanol (40 mL) and water (20 mL) at 100 C for 8 h to give 4-chloro-2-methoxybenzyl cyanide as a colorless oil (1.8 g, 36%) Step C
In a manner similar to the method described in Example lb, 4-chloro-2-methoxybenzyl cyanide (1.8 g, 10 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (2 g, 13 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (50 mL) at 50 C for 2 h to give (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-methoxy-pheny1)-acrylonitrile as a white powder (2.1 g, 65%).
Example 58b Preparation of intermediate rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester Cl F o OK
410. NH
1101 µµ
M. W. 535.49 C28}133C12FN203 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was roacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-methoxy-pheny1)-acrylonitrile (1.8 g, 5.6 mmol) prepared in Example 58a, AgF (1.7 g, 13 mmol), and triethylamine (2.8 g, 28 mmol) in dichloromethane (100 mL) at room temperature for 24 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methoxy-pheny1)-4-cyano-5 -(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.8 g, 60%).
Example 58c 1 0 Preparation of intermediate rac-(2S,3S,4R,5 S)-3 -(3 -chloro -2-fluoro-pheny1)-4-(4-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid = NH
11000 N w CI
M. W. 479.38 C24H25C12FN203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluor -pheny1)-4-(4-chloro-2-metho xy-p heny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carboxylic acid tert-butyl ester prepared in Example 58b (1.3 g, 2.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.5 g, 100%).
Example 58d Preparation of rac-(2S,3S,4R,5 S)-3-(3 -chloro-2-fluoro-pheny1)-4-(4-chloro -2-methoxy-p heny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F o OH
= NH
M. W. 566.50 C28H34C12FN304 In a manner similar to the method described in Examples 42c, 42d, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 58c (0.4 g, 0.67 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.25 g, 1.7 mmol), HATU
(0.4 g, 1.1 mmol) and iPr2NEt (0.6 g, 4.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.23 g, 61%).
FIRMS (ES-) rwrz Cala' for C28H34C12FN304+ H [(M+H )]: 566.1983. found:
566.1983.
Example 59a Preparation of intermediate [2-cyclohexyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester M. W. 239.36 C14H25NO2 In a manner similar to the method described in Example la, glycine tert-butyl ester (1.3 g, 10 mmol) was reacted with 2-c7yrclohexylacetaldebyde (Beiapharma) (1.3 g, 1) nimol) in CH2C12 at room temperature for 5 h to give [2-cyclohexyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.3 g, 96%).
Example 59b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester CI F n = r: NH
CI
M. W. 531.50 C29H33C12FN202 In a manner similar to the method described in Example lc, [2-cyclohexyl-eth-(E)-ylideneaminc]-acetic acid tert-butyl ester prepared in Example 59a (2.3 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-pheny1)-acrylonitrile (1.9 g, 6.5 mmol) prepared in Example 26a, AgF (1.7 g, 13 mmol), and triethylamine (2.6 g, 26 mmol) in dichloromethane (100 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.9 g, 55%).
Example 59c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
= NH
=0 CI 101 \\NI
M. W. 475.39 C25H25C12FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 59b (1.9 g, 3.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.1 g,99%).
Example 59d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F OH
NH OH
soro 4111 CI
M. W. 562.51 C29H34C12FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 59c (0.6 g, 1 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.3 g, 2 mmol), HATU (0.6 g, 1.6 mmol) and iPr2NEt (0.9 g, 7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.4 g, 71%).
FIRMS (ES-) filh Ca'cc' for C29H3402FN303+ H )1: 562.2034. found: 562.2033.
Example 60a Preparation of intermediate rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester CI F0 0?c/
= NH
CI
M. W. 531.50 C29H33C12FN202 In preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester as described in Example 59b, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester was obtained as the second product: a white foam, Yield, 1 g, 29%.
Example 60b Preparation of intermediate rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid = NH
=\µ
ci M. W. 475.39 C25H25C12FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 60a (0.4 g, 0.75 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.46 g, 100%).
Example 60c Preparation of rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide OH
= NH ilk "or Nµ Vir CI
M. W. 562.51 C29H34C12FN303 In a manner similar to the method described in Example 42e, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 60b (0.45 g, 0.75 mmol) was reacted with 2-((S)-2,2-dimethy141,3]dioxolan-4-y1)-ethylamine (0.23 g, 1.6 mmol), HATU (0.45 g, 1.2 mmol) and iPr2NEt (0.9 g, 7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.4 g, 95%).
FIRMS (IS) m/z Cala for C29H34C12FN303 11 RNI 11)']: 562.2034, found:
562.2033, Example 61a Preparation of intermediate (Z)-2-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-pheny1)-acrylonitrile ci N
M. W. 304.18 C16H11C12N0 In a manner similar to the method described in Example lb, 4-chloro-2-methoxybenzyl cyanide (2 g, 10 mmol) prepared in Example 58a Step B was reacted vith 3-chlorobenzaldehyde (2 g, 14 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (50 mL) at 50 C for 5 h to give (Z)-2-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-acrylonitrile as a white powder (1.9 g, 63%).
Example 61b Preparation of intermediate rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI 0 02( M. W. 517.50 C28H34C12N203 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-acrylonitrile (1.8 g, 5.9 mmol) prepared in Example 61a, AgF (1.7 g, 13 mmol), and triethylamine (2.8 g, 28 mmol) in dichloromethane (100 mL) at room temperature for 24 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.8 g, 60%).
Example 61c Preparation of intermediate rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid = NH F OH
CI ON
M. W. 461.39 C24H26C12N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 61b (2 g, 3.9 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.2 g, 98%).
Example 6111 Preparation of rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI 0 N_../-{'OH
OH
1101 P'µ
M. W. 548.51 C28H35C12N304 In a manner similar to the method described in Examples 42c, 42d, rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 61c (0.2 g, 0.35 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1.0 mmol), HATU (0.24 g, 0.63 mmol) and iPr2NEt (0.3 mL, 1.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.15 g, 84%).
FIRMS (ES') raiz Calcd fi,r C281435C12N304 H [(M A-1YI: 548.2078, found:
548,2077.
Example 62a Preparation of intermediate (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(2,3-difluoro-pheny1)-acrylonitrile F
ci M. W. 293.68 C15H7C1F3N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (4.5 g, 26 mmol) was reacted wiih 2,3-difluorobenzaldehyde (Aldrich) (4.5 g, 32 mmol), methanolic solution (25 wt%) of sodium methoxide (6.3 g, 29 mmol) in methanol (135 mL) at 50 C for 3 h to give (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(2,3-difluoro-pheny1)-acrylonitrile as a white powder (6.85 g, 88%).
Example 62b Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester F F _O
kJK
NH
1.1 CI F N
M. W. 507.00 C27H30C1F3N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was roacted with (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(2,3-difluoro-pheny1)-acrylonitrile (2.3 g, 8 mmol) prepared in Example 62a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.8 g, 44%).
Example 62c Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid F F
NH FOH
F. 11 1101 µ`N
M. W. 450.89 C23H22C1F3N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 62b (1.8 g, 3.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2 g, 100%).
i l RAS (ES') ailz Caticd thr C23H22C1F3N202 i [( Niti- F1)1: 451.1395, hund 451.1394.
Example 62d Preparation of rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide F F
= NH OH
110%µ" \`=
CI
M. W. 538.01 C27H31C1F3N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 62c(0.47 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.49 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.26 g, 58%).
II R MS (ES) iniz Ca icd for C27H31 Cl2F2N303-1- H [( M-i- 1: 538.2079. found:
538.207'7.
Example 62e Preparation of (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide F F
=
OH NH
CI
M. W. 538.01 C27H31C1F3N303 Rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.22 g) was separated by chiral SFC chromatography to provide chiral-(2R,35,4R,55)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (87 mg, 40%) and chiral-(2S,3R,4S,5R)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(2,3-difluoro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (87 mg, 40%).
Example 63a Preparation of intermediate (Z)-3-(3-bromo-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile Br F
CI
M. W. 354.58 C15H7BrC1F2N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (1.39 g, 8.2 mmol) was reacted with 3-bromo-2-fluorobenzaldehyde (Apollo)(2 g, 9.9 mmol), methanolic solution (25 wt%) of sodium methoxide (2 g, 9 mmol) in methanol (40 mL) at 50 C
for 3 h to give (Z)-3-(3-bromo-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile as a white powder (2.3 g, 79%).
Example 63b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester Br F
=
IS ""
Cl FN
M. W. 567.91 C27H30BrC1F2N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3-bromo-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (2.3 g, 6.5 mmol) prepared in Example 63a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2 g, 54%).
Example 63c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Br F of0H
= NH F-.7c,OH
w 140 µµ
CI FN
M. W. 5 1 1.80 C23H22BrC1F2N202.C2HF302 In a manner similar to the method described in Example ld, rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 63b (2 g, 3.5 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.1 g, 95%).
FIRMS (ES ') miz Calcd for C23H22BrC1F2N2021 H [(Mit 1) F]: 511.0594, found:
51 1.0595.
Example 63d Preparation of rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Br F
NH OH
=N\
CI
M. W. 598.91 C27H31BrC1F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 63c (0.5 1 g, 0.83 mmol) was reacted ,Nith 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU
(0.57 g, 1.49 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.2 g, 40%).
HRMS (ES-) mlz Calcd for C27H31BrC1F2N303+ H RN1+H )1: 598.1278, found:
598.1278.
Example 63e Preparation of (2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Br F 0 NH OH
1101P' CI
M. W. 598.91 C27H31BrC1F2N303 Rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.15 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (66 mg, 44%) and chiral (2S,3R,4S,5R)-3-(3-bromo-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (70 mg, 47%).
Example 64a Preparation of intermediate (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-pheny1)-acrylonitrile CI
N
CI
M. W. 292.14 C151-18C12FN
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (4.5 g, 26 mmol) was reacted with 3-chlorobenzaldehyde (Aldrich) (4.4 g, 32 mmol), methanolic solution (25 wt%) of sodium methoxide (6.6 mL, 29 mmol) in methanol (150 mL) at 50 C for 3 h to give (Z)-2-(4-Chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-acrylonitrile as a white powder (6.5 g, 84%).
Example 64b Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI ic,(0.-2( =N
CI F N ¨
M. W. 505.46 C27H3102FN202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was routed with (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-acrylonitrile (2.3 g, 8 mmol) prepared in Example 64a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.02 g, 25%).
Example 64c Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI
1101µ"µw CI FN
M. W. 449.36 C23H23C12FN202.C2HF302 In a manner similar to the method described in Example ld, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 64b (1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.88 g, 79%).
H RAS (ES-) miz Cated for C23H23C12FN202+ H k rv1+1-0-1: 449. I 194, found:
449.1194.
Example 64d Preparation of rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide NH OH
Cl .' 1"F NµI\I
M. W. 536.47 C27H32C12FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 64c (0.46 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 48%).
II R MS (ES) iniz Ca icd for C27H32C12FN303 H [d 1: 536,1 878, fOulld:
5361877.
Example 64e Preparation of (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
= NH OH
1101 µ µ1\1 CI
M. W. 536.47 C27H32C12FN303 Rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.15 g) was separated by chiral SFC chromatography to provide chiral (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (71 mg, 47%) and chiral-(2S,3S,4S,5R)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (70 mg, 47%).
Example 65a Preparation of intermediate (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3-fluoro-phenyl)-acrylonitrile CI
M. W. 275.69 C15I-I8C1F2N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (3.27 g, 19 mmol) was roacted with 3-fluorobenzaldehyde (Aldrich) (2.87 g, 23 mmol), methanolic solution (25 wt%) of sodium methoxide (4.83 mL, 21 mmol) in methanol (90 mL) at 50 C for 3 h to give (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(3-fluoro-pheny1)-acrylonitrile as a white powder (5.2 g, 98%).
Example 65b Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-pheny1)-pyrrolidine-2-carboxylic acid tert-butyl ester F
= NH
Cl F -M. W. 489.01 C27H31C1F2N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(3-fluoro-pheny1)-acrylonitrile (2.2 g, 8 mmol) prepared in Example 65a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-pheny1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.02 g, 26%).
Example 65c Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-pheny1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid = NH
"
CI F\\K
M. W. 432.90 C23H23C1F2N202.C2HF302 In a manner similar to the method described in Example ld, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 65b (1 g, 2.1 mmol) was reactcd with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 88%).
FIRMS (ES m/z Calcd for C23H23C1F2N202 i [(1\1 ]: 433.1489, found: 433.147.
Example 65d Preparation of rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide F OH
410'NH OH
CI 1.1%µF \\N
M. W. 520.02 C27H32C1F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 65c (0.46 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-3-(3-fluoro-pheny1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 48%).
HRMS ES)( Calcd for C27H32C1F2N303-4- 1-1 [(M+11)']: 520.2173, found:
520.2171, Example 66a Preparation of intermediate (Z)-3-(3-bromo-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile Br CI
M. W. 336.59 C15H8BrC1FN
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (1.9 g, 11 mmol) was reacted with 3-bromobenzaldehyde (Aldrich) (1.57 mL, 13.4 mmol), methanolic solution (25 wt%) of sodium methoxide (2.8 mL, 12 mmol) in methanol (50 mL) at 50 C for 3 h to give (Z)-3-(3-bromo-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile as a white powder (2.3 g, 60%).
Example 66b Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester Br o0?( IS ""
Cl FN
M. W. 549.92 C27H31BrCIFN202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3-bromo-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (2 g, 5.9 mmol) prepared in Example 66a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.3 g, 40%).
Example 66c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Br 0,0H
NH
F.tOH
CI F
M. W. 493.81 C23H23BrC1FN202.C2}1F302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 66b (1.2 g, 2.2 mmol) was reacted wid/ trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.1 g, 83%).
HRMS (ES' ) 1111Z Calcd for C23H23BrC1FN202¨ H [11\4-41)1: 493,0688, found:
493.0688.
Example 66d Preparation of rac-(2R,3R,4R,5 S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Br OH
NH
C I
M. W. 580.92 C27H32BrC1FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 66c (0.5 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.49 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.26 g, 55%).
FIRMS (ES-) m/z aled for C27H32BrC1FN303 11 [(4-41) j: 580.1373, found:
580,1372.
Example 67a Preparation of intermediate rac-(2S,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester Br 0 OK
NH
40 \\
01 F,,, M. W. 549.92 C27H31BrCIFN202 In preparation of rac-(2R,3R,4R,5 S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as described in Example 66b, rac-(2S,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester was obtained as the second product: a white foam (1.2 g, 37%).
Example 67b Preparation of intermediate rac-(2S,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Br 0 OH
= NH
1101:1 Cl F
M. W. 493.81 C23H23BrC1FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2S,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 67a (1.3 g, 2.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.2 g, 83%).
FIRMS (ES-) miz Cated for C23H23BrC1FN202¨ H RN44-1)1: 493.0688, found:
493.0689.
Example 67c Preparation of rac-(2S,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Br 0 OH
OH
NH
01 .' 1"F NµI\I
M. W. 580.92 C27H32BrC1FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2S,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 67b (0.5 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.49 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2S,3R,4R,5S)-3-(3-bromo-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 44%).
IIRMS (ES') mlz Ca icd for C27H32BrC1FN303-- H [(M-141)1: 580.1373, found:
580.1372.
Example 68a Preparation of intermediate (Z)-2-(4-Chloro-2-fluoro-pheny1)-3-(3,4-dichloro-pheny1)-acrylonitrile ci CI
=1\1 ci M. W. 326.59 C15H7C13FN
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenyl acetonitrile (4.5 g, 26 mmol) was reacted wiLh 3,4-dichlorobenzaldehyde (Aldrich) (5.5 g, 32 mmol), methanolic solution (25 wt%) of sodium methoxide (6.6 mL, 29 mmol) in methanol (150 mL) at 50 C for 3 h to give (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(3,4-dichloro-pheny1)-acrylonitrile as a white powder (6.5 g, 76%).
Example 68b Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI
CI 410, NH
CI F N
M. W. 539.91 C27H30C13FN202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was roacted with (Z)-2-(4-ehloro-2-fluoro-pheny1)-3-(3,4-dichloro-pheny1)-acrylonitrile (2.6 g, 8 mmol) prepared in Example 68a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rae-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-earboxylic acid tert-butyl ester as a white foam (1.7 g, 39%).
Example 68c Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI
CI = NH
F. 11 CI FN
M. W. 483.80 C23H22C13FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 68b (1.7 g, 3.1 mmol) was reacted with trifluoroacetic acid in diehloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.8 g, 96%).
Example 68d Preparation of rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI
OH
CI NH
[1011µ"
CI
M. W. 570.92 C27H31C13FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 68c (0.5 g, 0.84 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-3-(3,4-dichloro-pheny1)-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.28 g, 59%).
II R MS (ES) iniz Ca icd for C27H31C13FN303 H [(N.4-14)1: 570,1488, tbimd:
570.1489.
Example 69a Preparation of intermediate (Z)-3-(3-chloro-4-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile CI
F
N
M. W. 308.99 C15H7C12F2N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (3.3 g, 19 mmol) was reacted wi 4-chloro-3-fluoro-benzaldehyde (Aldrich) (3.65 g, 23 mmol), methanolic solution (25 wt%) of sodium methoxide (4.8 mL, 21 mmol) in methanol (90 mL) at 50 C for 3 h to give (Z)-3-(3-chloro-4-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile as a white powder (3 g, 50%).
Example 69b Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI 1eØ1 F 410, NH
101P' Cl FN
M. W. 523.46 C27H30C12F2N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was roacted with (Z)-3-(3-chloro-4-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 69a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1 g, 24%).
Example 69c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Cl 0 OH
= NH FOH
1101 .
CI FN
M. W. 467.35 C23H22C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 69b (1 g, 1.9 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 90%).
Example 69d Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide NHOH
Cl M. W. 554.46 C27H31C12F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 69c (0.28 g, 0.48 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.21 g, 1.44 mmol), HATU (0.33 g, 0.87 mmol) and iPr2NEt (0.42 mL, 2.4 mmol) in CH2C12 at room temperature for h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.18 g, 77%).
15 HR IS ES)( rniz Ca tat for C27H31C13FN303 H [d M-1-11) 554.1784, tbulld: 554.1785.
Example 69e Preparation of (2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
F =
NH OH
CI
M. W. 554.46 C27H31C12F2N303 Rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.14 g) was separated by chiral SFC chromatography to provide chiral (2R,3R,4R,55)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (61 mg, 44%) and chiral-(2S,3S,4S,5R)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (61 mg, 44%).
Example 70a Preparation of intermediate (Z)-3-(4-bromo-thiophen-2-y1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile Br \
N
M. W. 342.62 C13H6BrC1FNS
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (4.05 g, 24 mmol) was reacted with 4-bromo-2-thiophenecarboxaldehyde (Aldrich) (6.08 g, 29 mmol), methanolic solution (25 wt%) of sodium methoxide (6 mL, 26 mmol) in methanol (90 mL) at 50 C for 3 h to give (Z)-3-(4-bromo-thiophen-2-y1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile as a light yellow solid (5.2 g, 64%).
Example 70b Preparation of intermediate rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester Br 0,1;:;>( is I NH
\'µ
Cl FN
M. W. 555.94 C25H29BrC1FN202S
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(4-bromo-thiophen-2-y1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.7 g, 8 mmol) prepared in Example 70a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.9 g, 20%).
Example 70c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Br OH
I NH
1101 "
CI F N
M. W. 499.83 C21H21BrC1FN202S.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 70b (0.9 g, 1.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a light blue solid (0.9 g, 92%).
Example 70d Preparation of rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Br I NH OH
CI
M. W. 586.95 C25H30BrC1FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 70c (0.2 g, 0.33 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.14 g, 1 mmol), HATU
(0.22 g, 0.58 mmol) and iPr2NEt (0.28 mL, 1.63 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-y1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.15 g, 80%).
FIRMS (ES) 111/Z Caled for C25H30BrC1FN303¨ H Rivii-Fhl: 586.0937, found:
586.0935.
Example 71a Preparation of intermediate (Z)-2-(4-Chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-acrylonitrile Cl F
F
CI
M. W. 360.14 C16H7C12F4N
Step A
A mixture of 3-chloro-4-(trifluoromethyObenzyl alcohol (Synquest) (4.77 g, 23 mmol) and activated Mn02 (19.5 g, 230 mmol) in 1,2-dichlorethane (80 mL) was heated and stirred at 80 C
for 3 h. The mixture was cooled to room temperature and filtered through a short pad of celite.
The celite was washed with dichloromethane, and ethyl acetate. The filtrates were combined, concentrated, dried under reduced pressure to give 3-chloro-4-(trifluoromethyl)benzaldehyde as a light yellow oil (2.8 g, 60%).
Step B
In a manner similar to the method described in Example lb, 4-chloro-2-methylbenzyl cyanide (1.9 g, 11 mmol) was reacted with 3-chloro-4-(trifluoromethyl)benzaldehyde (2.8 g, 14 mmol), methanolic solution (25 wt%) of sodium methoxide (2.8 mL, 12 mmol) in methanol (50 mL) at 50 C for 5 h to give (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-acrylonitrile as a yellow solid (2.45 g, 61%).
Example 71b Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester FCI ?( F = NH
`µ
CI F r, ¨
M. W. 573.46 C281-130C12F4N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-acrylonitrile (2.5 g, 6.9 mmol) prepared in Example 71a, AgF (1 g, 8 mmol), and triethylamine (2.4 mL, 17 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 30%).
Example 70c Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Cl 0 OH
F
F - NH
00%µ"
CI FN
M. W. 517.35 C24H22C12F4N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 70b (1.2 g, 2.1 mmol) was reacted µNitli trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as solid (1.1 g, 83%).
Example 71d Preparation of (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide Cl F = NH OH
M. W. 604.47 C28H31C12F4N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-4-trifluoromethyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 71c (0.22 g, 0.35 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1.05 mmol), HATU (0.24 g, 0.63 mmol) and iPr2NEt (0.3 mL, 1.74 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-trifluoromethyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.14 g, 73%).
HRMS ES iz Caled for C28H31 Cl2F4N303 H [(4+1-1)']: 604.1752, found:
604.1748.
Example 72a Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide Cl = NH
1101""
Cl M. W. 554.46 C27H31C12F2N303 Step A
In a manner similar to the method described in Example 3a Step A to C, (4R)-(-)-4-(2-hydroxyethyl)-2,2-dimethy1-1,3-dioxolane (Aldrich) (4.91 g, 33.6 mmol) was reacted with methanesulfonyl chloride (3.12 mL, 40.3 mmol) and triethylamine (9.34 mL, 67 mmol) in dichloromethane, then reacted with NaN3 (10.7 g, 0.16 mol) in N,N-dimethylformamide, then treated with Pt02 and H2 (50 psi) in ethyl acetate to give 24(R)-2,2-dimethy141,3]dioxolan-4-y1)-ethylamine as a brown oil (4.4 g, 90% for three steps).
Step B
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 69c (0.2 g, 0.48 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1.0 mmol), HATU
(0.23 g, 0.62 mmol) and iPr2NEt (0.3 mL, 1.72 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide as a white solid (0.11 g, 74%).
1-IRMS (IS) miz Calcd for C27H3103FN3034-11 [(/1-1-H)]: 554.1784, [bind:
554.176.
Example 72b Preparation of (2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide Cl NHOH
" µ,µ
Cl M. W. 554.46 C27H31C12F2N303 Rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide (80 mg) was separated by chiral SFC chromatography to provide chiral (2R,3R,4R,5S)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (35 mg, 44%) and chiral (25,3S,4S,5R)-3-(3-chloro-4-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (35 mg, 44%).
Example 73a Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide CI F
.NH OH
1101 µ
CI
M. W. 554.46 C27H31C12F2N303 In a manner similar to the method described in Example 72a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 53b (0.44 g, 0.769 mmol) was t-acted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.33 g, 2.3 mmol), HATU (0.52 g, 1.36 mmol) and iPr2NEt (0.66 mL, 3.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide as a white solid (0.29 g, 68%).
FIRMS (ES') ni/z. CaLc.d fi,r C27H31C12F2N303 H [( M I 1) ]: 554.1 784, fbund:
554.1783.
Example 73b Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide CI F
NH OH
1101P' Cl M. W. 554.46 C27H31C12F2N303 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide (0.28 g) was separated by chiral SFC chromatography to provide chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (109 mg, 39%) and chiral-(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (109 mg, 39%).
Example 74 Preparation of rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide Cl 0 NH OH
Cl M. W. 536.47 C27H32C12FN303 In a manner similar to the method described in Example 72a, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid (0.2 g, 0.36 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1.07 mmol), HATU (0.24 g, 0.64 mmol) and iPr2NEt (0.31 mL, 1.78 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 54%).
R. MS (ES') ni/z. CaLcd for C27H32C12FN303 1 [t M-11-01: 5:36,1878, fund:
5361880.
Example 75 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide CI F
NH OH
CI
M. W. 536.47 C27H32C12FN303 In a manner similar to the method described in Example 72a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid (0.2 g, 0.36mmol) was reacted wiLl/ 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1.07 mmol), HATU (0.24 g, 0.64 mmol) and iPr2NEt (0.31 g, 1.78 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 54%).
HRMS (ES') Calcd for C27H32C12FN303+1-1 [(Ni+H)l: 536.1878. found:
536.1880.
Example 76 Preparation of rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide Cl 0 OH
OH
NH
Cl 0 N
M. W. 548.51 C28H3502N304 In a manner similar to the method described in Example 72a, rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid (0.2 g, 0.35 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.15 g, 1.0 mmol), HATU (0.24 g, 0.63 mmol) and iPr2NEt (0.3 mL, 1.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 57%).
[IRAS (ES') raiz Cadcd for C281-135C12N304 1 1 [(M F11) j: 548.2078, found:
548,2074.
Example 77 Preparation of rac-(2R,3R,4R,5 S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide NH OH
CI
M. W. 518.48 C27H33C12N303 In a manner similar to the method described in Example 72a, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid (0.2 g, 0.37 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.159 g, 1.1 mmol), HATU (0.25 g, 0.66 mmol) and iPr2NEt (0.32 mL, 1.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide as a white solid (0.15 g, 81%).
HMIS (ES) miz ULU ibr C27H33C12N303 H [(Mi II) j: 518.1972, found: 518.1972.
Example 78a Preparation of intermediate [3,3,4-trimethyl-pent-(E)-ylideneamino]- acetic acid tert-butyl ester M. W. 241.38 C14H27NO2 Step A
To a solution of ethyl 3,3-dimethylacrylate (Aldrich) (6.98 g, 54 mmol) in anhydrous tetrahydrofuran (60 mL) was added chlorotrimethylsilane (12 mL, 70 mmol), CuI
(1.5 g, 8 mmol) under nitrogen. The mixture was stirred and the temperature was cooled to -20 C. To the stirring mixture was slowly added a tetrahydrofuran solution (2 N) if isopropylmagnesium chloride (40 mL, 80 mmol) during a period of 30 min while maitining the temperature below -10 C. After the addition was finished, the reaction mixture was gradually warmed to 0 C and stirred at 0 C for 3 h. Aqueous saturated NH4C1 solution was added to quench the reaction, and the mixture was extracted with ethyl acetate and ethyl ether. The organic layers were combined, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;20, 1;10) to give 3,3,4-trimethyl-pentanoic acid ethyl ester as a colorless oil (7 g, 75%).
Step B
To a solution of 3,3,4-trimethyl-pentanoic acid ethyl ester (7 g, 41 mmol) in anhydrous ethyl ether (100 mL) at 0 C was added a ethyl ether solution (1 M) of LiA1H4 (67 mL, 67 mmol) under nitrogen. The reaction mixture was stirred at 0 C for 1 h, then poured into a ice-water.
The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated to give 3,3,4-trimethyl-pentan-1-ol as a colorless oil (5.4 g, 100%).
Step C
To a solution of 3,3,4-trimethyl-pentan-l-ol (5.4 g, 41 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (22 gõ 52 mmol) The reaction mixture was stirred at room temperature for 3 h. Aqueous Na2S03 solution was added to quench the reaction.
The organic layers were separated, washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes=1:30) to give 3,3,4-trimethyl-pentanal as a colorless oil (Yield: 1.1 g, 21%).
Step D
In a manner similar to the method described in Example la, glycine tert-butyl ester (1g, 7.7 mmol) was reacted with 3,3,4-trimethyl-pentanal (i .1 gõ 8 filrnoi) in CH2C12 at room temperature for 5 h to give [3,3,4-trimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.5 g, 80%).
Example 78b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F cle0?( NH
sow.
M. W. 555.51 C29H34C12F2N202 In a manner similar to the method described in Example lc, [3,3,4-trimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 78a (1.5 g, 6.2 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (1.1 g, 3.5 mmol) prepared in Example 52a, AgF (1.2 g, 9.5 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 56%).
Example 78c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
NH FO
"
1.1 CI FN
M. W. 495.40 C25H26C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 78b (1.1 g, 2 mmol) was reactd with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (1.1 g, 91%).
Example 78d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI F
NHOH
1101P \N=
CI
M. W. 582.52 C29H35C12F2N303 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 78c (0.55 g, 0.9 mmol) was reactedvith 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.39 g, 2.7 mmol), HATU
(0.62 g, 1.6 mmol) and iPr2NEt (0.78 mL, 4.5 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.32 g, 62%).
H RMS (ES-) mlz Cated for C29H35C12F2N303,-- H [( M+1-1)1: 582.2097, found:
582.2095.
Example 78e Preparation of (2R,3S,4R,55)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide NHOH
1101P'µ
CI
M. W. 582.52 C29H35C12F2N303 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.25 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 40%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 40%).
Example 79a Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide CI F
NH OH CI
F
M. W. 582.52 C29H35C12F2N303 In a manner similar to the method described in Example 72a rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 78c (0.55 g, 0.9 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.39 g, 2.7 mmol), HATU (0.62 g, 1.6 mmol) and iPr2NEt (0.78 mL, 4.5 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide as a white solid (0.3 g, 58%).
FIRMS (ES') rwrz Cala' for C29H3502F2N303-,- H [0'0+H )]: 582.2097, found:
582.2094.
Example 79b Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide CI F OH
= N H OH
1101 µ
CI
M. W. 582.52 C29H35C12F2N303 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-buty1)-amide (0.29 g) was separated by chiral SFC chromatography to provide chiral (2R,35,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.12 g, 41%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2,3-trimethyl-buty1)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.12 g, 41%).
Example 80a Preparation of intermediate [3,3-dimethyl-pent-4-en-(E)-ylideneamino]-acetic acid tert-butyl ester M. W. 225.33 C13H23NO2 Step A
To a solution of methyl 3,3-dimethy1-4-pentenoate (Aldrich) (6.1 g, 43 mmol) in anhydrous ethyl ether (100 mL) at 0 C was added a tetrahydrofuran solution (2 M) of LiA1H4 (32 mL, 64 mmol) under nitrogen. The reaction mixture was stirred at 0 C for 1 h, then poured into a ice-water.
The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated to give 3,3-dimethyl-pent-4-en-1-ol as a colorless oil (4.8 g, 98%).
Step B
To a solution of oxalyl chloride (5.9 g, 46 mmol) (Aldrich) in dichloromethane (60 mL) at -78 C
was added the solution of dimethyl sulfoxide (6.6 mL, 92 mmol) in dichloromethane dropwise.
After 5 mins, the solution of 3,3-dimethyl-pent-4-en-l-ol (4.8 g, 42 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min.
Triethylamine (21 mL, 0.15 mol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. The water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3,3-dimethyl-pent-4-enal as a colorless oil (Yield: 3.2 g, 68%).
Step C. In a manner similar to the method described in Example la, glycine tert-butyl ester (1.3 g, 10 mmol) was t-acted with 3,3-dimethyl-pent-4-enal (I ,2 g, I I mnio I) in CH2C12 at room temperature for 18 h to give [3,3-dimethyl-pent-4-en-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.1 g, 93%).
Example 80b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F (:)/Cy =E NH
110(µ ,,, I
CI F\\
M. W. 535.47 C281-130C12F2N202 In a manner similar to the method described in Example lc, [3,3-dimethyl-pent-4-en-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 80a (2.1 g, 9.3 mmol) was reacted µ;µ,ii.1/ (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2 g, 6.4 mmol) prepared in Example 52a, AgF (0.9 g, 7.1 mmol), and triethylamine (1.5 g, 15 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.98 g, 56%).
Example 80c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Cl F 0/0H
= NH FO
"
CI FN
M. W. 479.36 C24H22C12F21\1202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 80b (1.0 g, 1.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.0 g, 91%).
Example 80d Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide CI F
= NH (31 101µµ"
CI F
M. W. 606.55 C311-135C12F2N303 In a manner similar to the method described in Example 42c, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 80c (1.0 g, 1.69 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.73 g, 5.0 mmol), HATU (1.15 g, 3 mmol) and iPr2NEt (1.46 mL, 8.4 mmol) in CH2C12 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide as a white solid (0.82 g, 80%).
Example 80e Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide = NH OH
OP
F
C
I
M. W. 566.47 C28H31C12F2N303 In a manner similar to the method described in Example42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 80d (0.36 g, 0.59 mmol) was reacted with aqueous HC1 solution (1 N, 1 mL) in tetrahydrofuran (10 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.32 g, 95%).
I RMS (ES') raiz Cated for C28H3102F2N303 1 [( M I 1)]: 566.1784, tbund:
566.1786.
Example 81a Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide Of NH
101""
CI
M. W. 608.56 C31H37C12F2N303 A suspension of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-but-3-eny1)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 80d (0.4 g, 0.65 mmol) and Pt02 (0.2 g) in ethyl acetate (15 mL) was vigorously shaken tinder 147 atornosphere (30 psi) for 1 h. The mixture was filtered through a short pad of celite, and the filtrate was concentrated to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide as a white gum (0.33 g, 83%).
Example 81b Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI F
.NH OH
1101 µ
CI
M. W. 568.49 C28H33C12F2N303 In a manner similar to the method described in Example 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 81a (0.41 g, 0.67 mmol) was reacted with aqueous HC1 solution (1 N, 1 mL) in tetrahydrofuran (10 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.38 g, 99%).
HRMS ES)( n1,17 Caled for C28H33C12F2N303-4- H [(Mi-1-l) ]: 568.1940, found: 568.1942.
Example 82a Preparation of intermediate [3-methy1-3-phenyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester M. W. 275.39 C17H25NO2 Step A
To a solution of 3-methy1-3-phenylbutanoic acid (ChemBridge) (4.46 g, 25 mmol) in anhydrous tetrahydrofuran (150 mL) at 0 C was added a tetrahydrofuran solution (1 M) of BH3.THF
(Aldrich, 50 mL, 50 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 3 h, then concentrated. The residue was partitoned between ethyl acetate and water. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated to give 3-methy1-3-phenyl-butan-1-ol as a colorless oil (4.1 g, 100%).
Step B
To a solution of oxalyl chloride (1.7 g, 13 mmol) (Aldrich) in dichloromethane (50 mL) at -78 C
was added the solution of dimethyl sulfoxide (1.9 mL, 27 mmol) in dichloromethane (10 mL) dropwise. After 5 mins, the solution of 3-methy1-3-phenyl-butan-l-ol (2 g, 12 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (6.1 mL, 44 mol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. The water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3-methyl-3-phenyl-butyraldehyde as a colorless oil (Yield: 1.8 g, 90%).
Step C
In a manner similar to the method described in Example la, glyeine tert-butyl ester (1.3 g, 10 mmol) was reacted with 3-methyl-3-phenyl-butyraldehyde (1.8 g, I 1 rornol) in CH2C12 at room temperature for 18 h to give [[3-methyl-3-phenyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.3 g, 93%).
Example 82b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-ehloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
o.O= 1\111H
M. W. 585.53 C32H32C12F2N202 In a manner similar to the method described in Example lc, [[3-methy1-3-phenyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 82a (2.3 g, 8.3 mmol) was reacted %Nit)/ (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.4 g, 7.7 mmol) prepared in Example 52a, AgF (0.7 g, 5.5mmol), and triethylamine (2.1 g, 21 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methyl-2-phenyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1 g, 22%).
Example 82c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Ci F
= NH FLÇO
F
CI F µN
M. W. 529.42 C28H24C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 82b (1.0 g, 1.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methy1-2-phenyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.0 g, 91%).
Example 82d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methyl-2-phenyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH OH
OP' *CI
M. W. 616.53 C32H33C12F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 82c (0.35 g, 0.54 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.24 g, 1.62 mmol), HATU (0.37 g, 0.98 mmol) and iPr2NEt (0.47 mL, 2.7 mmol) in CH2C12 at room temperature for h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methyl-2-phenyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.21 g, 66%).
20 FIRP,AS (ES Caled for C32H33C12F2N303 II [0,114-1)' j:
616.1940, found: 61 6 1939, Example 83a Preparation of intermediate (Z)-3-(3-chloro-5-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile ci ci 40 M. W. 308.99 C15H7C12F2N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (3.4 g, 20 mmol) was reacted with 3-chloro-5-fluoro-benzaldehyde (Aldrich) (3.77 g, 24 mmol), methanolic solution (25 wt%) of sodium methoxide (4.99 mL, 22 mmol) in methanol (90 mL) at 50 C for 3 h to give (Z)-3-(3-chloro-5-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile as a white powder (5.5 g, 90%).
Example 83b Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester CI ofiCy NH
F
CI F N
M. W. 523.46 C27H30C12F2N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-5-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 83a, AgF (1.0 g, 8 mmol), and triethylamine (2.8 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 29%).
Example 83c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI 10,0H
= NH FFOH
F
"
CI =F N
M. W. 467.35 C23H22C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 83b (1.2 g, 2.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.3 g, 97%).
Example 83d Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-phenyl)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI
= NH OH
F Ow' CI
M. W. 554.46 C27H31C12F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 83c (0.4 g, 0.69 mmol) was reacted ,vvith 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.3 g, 2.06 mmol), HATU
(0.47 g, 1.24 mmol) and iPr2NEt (0.6 mL, 3.44 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.13 g, 35%).
HRMS (ES-) miz Caled for C27H31 Cl3FN303+ H M+1-01: 554.1784, found: 554.1782.
Example 84a Preparation of intermediate (Z)-3- {2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl} -2-(4-chloro-2-fluoro-phenyl)-acrylonitrile -"F CI
CI
M. W. 466.46 C23H26C12FN 025i Step A
To a solution of 5-chlorosalicylaldehyde (2 g, 12.8 mmol) (Aldrich) in N,N-dimethylformamide (40 mL) was added K2CO3 (5.3 g, 38 mmo), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (3.67 g, 15 mmol, Aldrich). The reaction mixture was heated at 60 C for 18 h.
The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, concentrated, and the residue was purified by chromatography (Et0Ac:Hexanes=1:8, then 1:4) to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde as a brown oil (Yield 3.8 g, 91%).
Step B
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (1.7 g, 10 mmol) was reacted µNiill 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde (3.8 g, 12.5 mmol), methanolic solution (25 wt%) of sodium methoxide (2.5 mL, 11 mmol) in methanol (60 mL) at 50 C for 3 h to give (Z)-3- {242-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyll -2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a yellow oil (4.5 g, 80%).
Example 84b Preparation of intermediate rac-(2R,3S,4R,5S)-3- {2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro -phenyl} -4-(4-chloro -2-fluoro-pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carboxylic acid tert-butyl ester 0 Ox' = NH
CI /10,0, CI F N
M. W. 679.78 C35H49C12FN204Si In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl} -2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (3.7 g, 8 mmol) prepared in Example 84a, AgF (1.0 g, 8 mmol), and triethylamine (2.8 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3- {2- [2-(tert-butyl-dimethyl-silanyloxy)-etho xy] -5-chloro -phenyl} -4-(4-chloro -2-fluor -pheny1)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carboxylic acid tert-butyl ester as a white foam (1.0 g, 18%).
Example 84c Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-345-chloro-2-(2-hydroxy-ethoxy)-pheny1]-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid HO
0 (-1 OH
= NH
"
CI *u"
CI FN
M. W. 509.47 C25H27C12FN204.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(242-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenylI -4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 84b (1.0 g, 1.5 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-[5-chloro-2-(2-hydroxy-ethoxy)-pheny1]-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.9 g, 98%).
Example 84d Preparation of rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-[5-chloro-2-(2-hydroxy-ethoxy)-pheny1]-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide HO
OH
= NH
CI al \\N
LIW. F
M. W. 596.53 C29H36C12FN305 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-[5-chloro-2-(2-hydroxy-ethoxy)-pheny1]-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 84c (0.4 g, 0.64 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.28 g, 1.93 mmol), HATU (0.44 g, 1.15 mmol) and iPr2NEt (0.56 mL, 3.21 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-345-chloro-2-(2-hydroxy-ethoxy)-pheny1]-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (50 mg, 13%).
I R. MS (ES') raiz CaIed for C29H36C12FN305 I H [( [VII / 01: 596,2089, tbund:
596.2087.
Example 85a Preparation of intermediate (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-acrylonitrile oI Ati Cl 1.1 CI
M. W. 322.17 C16H10C12FN 0 In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (2.8 g, 16.6 mmol) was reacted with 5-chloro-2-methoxybenzaldehyde (Matrix) (3.4 g, 19.9 mmol), methanolic solution (25 wt%) of sodium methoxide (4.17 mL, 18 mmol) in methanol (100 mL) at 50 C for 3 h to give (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-acrylonitrile as a white solid (2.0 g, 37%).
Example 85b Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester NH
CI Ow CI F N
M. W. 535.49 C281133C12FN203 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (1.1 g, 5 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-acrylonitrile (1.28 g, 4 mmol) prepared in Example 85a, AgF (0.76 g, 6 mmol), and triethylamine (1.38 mL, 10 mmol) in dichloromethane (100 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.3 g, 14%).
Example 85c Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid NH
"
OH
CI 0 00"
CI F
M. W. 479.38 C24H25C12FN203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 85b (0.3 g, 0.56 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.32 g, 97%).
Example 85d Preparation of rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide OH
410' NH
ci ci F
M. W. 566.51 C28H34C12FN304 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 85c (0.32 g, 0.54 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.23 g, 1.62 mmol), HATU (0.37 g, 0.98 mmol) and iPr2NEt (0.47 mL, 2.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (65 mg, 21%).
FIRMS (ES') libiZ Calcd for C28H3402FN304+ I-1 [(11/44+1-1)1: 566.1983. found:
566.1984.
Example 86 Preparation of rac(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (quinolin-3-ylmethyl)-amide CI ON
= NH N
CI
M. W. 571.56 C33H32C12N40 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol) prepared in Example ld was reacted with quinolin-3-yl-methylamine (47.5 mg, 0.3 mmol), HATU (76.0 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight. to give rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (quinolin-3-ylmethyl)-amide (54.4 mg, 47.5 %) as a white powder.
HRMS (ES') TrbiZ Calcd for C33H32C12N40 + H [(1A+H)']: 571.2026, found:
571.2027.
Example 87 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 4-trifluoromethyl-benzylamide CI
=- NH
\\
C I
M. W. 588.498 C31f130C12F3N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted ,õ-vit1-14-trifluoromethylbenzyl amine (52.5 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 4-trifluoromethyl-benzylamide (58.1 mg, 58.04 %).
HRIMS (ES `) ntlz Caled for C311-130C12F3N30+ H [(M+HY I: 588.1791, found:
588.1788.
Example 88 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 3-trifluoromethyl-benzyl amide F F
CI
H
NH
M. W. 588.498 C31I-130C12F3N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 3-trifluoromethylbenzyl amine (52.55 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 3-trifluoromethyl-benzyl amide (26.2 mg, 26.2 %).
fiRMS (ES') rrik Ca led =for C311-130C12F3N30-i H [(NU II) ]: 588.179i, found:
588.1788.
Example 89 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 4-hydroxy-benzylamide CI
= NH OH
CI
M. W. 536.51 C30I-131C12N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 4-hydroxybenzyl amine (36.9 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 4-hydroxy-benzylamide (45.1 mg, 45.0 %).
FIRMS (ES-) 111/Z Ca'cc' for C301-131C12N302 4- H [(M+H)--): 536.1866, found:
536.1866.
Example 90 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 3-iodo-benzylamide CI
410. NH
CI
M. W. 646.393 C30H30C121N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 3-iodobenzyl amine (68.92 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid 3-iodo-benzylamide (44.1 mg, 34.1 %).
FIRMS (ES') raiz Caled lbr C301-13002IN30 i RM I 1 Y1:646,0884, found:
646.0881.
Example 91 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-ethyl-butyl)-amide CI n NH
w*, CI
M. W. 514.54 C29H37C12N30 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example ld was reacted with 2-ethyl butyl amine (30.3 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-pheny1)-4-(4-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (2-ethyl-butyl)-amide (34 mg, 33.04 %).
FIRMS (ES ') rwrz Calcd for C29H37C12N30 + H [(1V1-1-FI)]:5 14.2387, found:
514.2385.
Example 92 Preparation of rac-4- [(2R,3S ,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano -5 -(2,2-dimethyl-propy1)-pyrro lidine-2-carbonyl] -amino} -p ip eridine-1 -carboxylic acid tert-butyl ester )ro,ro r LYI
CI F
41 7. NH
0 ' Cl F N
M. W. 649.61 C33H40C12F2N403 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (1.8 g, 3.1 mmol) was reacted ,õ-vith 4-Amino-piperidine-1-carboxylic acid tert-butyl ester(Aldrich, 931 mg, 4.65 g, 4.65 mmol), HATU (2.12 g, 0.92 mmol) and iPr2NEt (2.7 mL, 15.5 mmol) in CH2C12 at room temperature overnight, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give a white solid (0.758 g, 38%).
FIRMS (ES ) m/z Calcd for C33H40C12F2N403 11 RM H j: 649.2519, found:
649.2518.
Example 93 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic acid r `Y) Ci F Hojc:
NH F F
CI F N
M. W. 549.49 C281-132C12F2N40. C2HF302 To a stirred solution of a mixture of TFA/CH2C12(5 mL/10 mL), rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carbonyll-aminol-piperidine-1-carboxylic acid tert-butyl ester (example 92, 510 mg, 0.79 mmol) was added and the mixture was stirred at rt for 15 min. The solvent was removed and the residue dried to give a white solid after precipation from methylene chloride and ethyl acetate. 492 mg.
I R. MS (ES' ) raiz Ca Icd for C28H32C12F2N40 1 1 RM F II) j: 549.19()4, found: 549,1994, Example 94 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1-methanesulfonylpiperidin-4-y1)-amide rNi CI F
= NH
Cl FN
M. W. 627.58 C29H34C12F2N403S
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic acid (80 mg, 0.10 mmol) in methylene chloride (10 mL), methanesulfonyl chloride (14 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the misture was stirred at rt for 1 hr. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crued which was chromatographied on an ISCO machine (0-10% Et0Ac/CH2C12) to give a white solid. 53 mg.
HR MS (ES-) nIz Caled fir C29H34C12F2N403S H 627.1770, found: 627.1766.
Example 95 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1-methyl-carbonyl-piperidin-4-y1)-amide o (NI
CI F NH
w CI F N
M. W. 591.53 C30H34C12F2N403 To a stirred solution of (2R,3S,4R,5S)-3-(3-ehloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetie acid (80 mg, 0.10 mmol) in methylene chloride (10 mL), acetic anhydride (18 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the misture was stirred at rt for 1.5 hr. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crued which was chromatographied on an ISCO machine (0-10% Et0Ac/CH2C12) to give a white solid. 58 mg.
HRMS (ES-) miz Caled lig C301-13402F2N403,- H[( M+H)1: 591.2100, found:
591.2099.
Example 96 Preparation of rac-(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid (1-benzoyl-piperidin-4-y1)-amide o ç) CI F NH
= NH
10 CI F "N
M. W. 653.59 C35H36C12F2N402 To a stirred solution of (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic acid (80 mg, 0.10 mmol) in methylene chloride (10 mL), benzoyl chloride (21 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the misture was stirred at rt for 1 hr. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crued which was chromatographied on an ISCO machine (0-10% Et0Ac/CH2C12) to give a white solid. 36 mg. HRMS (ES') m/z Caled fir C35H36C12F2N402 H 4 I-1 )' j: 653.2256, found: 653.2253.
Example 97 Preparation of rac-4- { [(2R,3S ,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrro lidine-2-carbonyl] -amino} -p ip eridine-1-carboxylic acid isopropylamide I rN1 CI F NH
= NH
Cl F N
M. W. 634.60 C32H39C12F2N502 To a stirred solution of (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic (80 mg, 0.10 mmol) in methylene chloride (10 mL), 2-propyl isocyante (18 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the misture was stirred at rt for 1 h. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crued which was chromatographied on an ISCO machine (0-10% Et0Ac/CH2C12) to give a white solid.
R MS (1:,:S') rah Ca[cd for C32H39C12F2N502 H [(1v1-f-H)`]: 634.2520, found:
634.2522 Example 98a Preparation of intermediate (Z)-3-(5-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile F
1111111 Cl CI
M. W. 310.13 C15H7C12F2N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (2.8 g, 16.6 mmol) was reacted with 5-chloro-2-fluorobenzaldehyde (Alfa) (3.2 g, 19.9 mmol), methanolic solution (25 wt%) of sodium methoxide (4.17 mL, 18 mmol) in methanol (100 mL) at 50 C for 3 h to give (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-acrylonitrile as a off white solid (3.5 g, 68.6%).
Example 98b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester NH
CI
CI F N
M. W. 523.46 C27H30C12F2N202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.2 g, 10 mmol) was routed with (Z)-2-(4-chloro-2-fluoro-pheny1)-3-(5-chloro-2-methoxy-pheny1)-acrylonitrile (2.46 g, 8 mmol) prepared in Example 98a, AgF (1.52 g, 12 mmol), and triethylamine (2.78 mL, 20 mmol) in dichloromethane (1500 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 26%).
Example 98c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid F n OH
== NH
"
CI
CI F N
M. W. 467.35 C23H22C12F 12N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 98b (1.1 g, 2.1 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.1 g, 90%).
Example 98d Preparation of rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide F
NH OH
CI ai M. W. 554.46 C27H31C12F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 98c (0.4 g, 0.68 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.3 g, 2.06 mmol), HATU
(0.47 g, 1.24 mmol) and iPr2NEt (0.6 mL, 3.44 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-eyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.36 g, 80%).
HR I\S ES)( Trilz Ca icd for C27H31C12F2N303-1- H [( 554.1784. found: 554.1782.
Example 99a Preparation of intermediate [3-cyclopropy1-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester 00y-U,v, M. W. 239.36 C14H25NO2 Step A
To a suspension of CuI (7.61 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) at -50 C was added cyclopropylmagnesium bromide (0.5 M, 160 mL, 80 mmol) during a period of 15 min.
After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to -50 C, a tetrahydrofuran solution (50 mL) of diethyl isopropylidenemalonate (Aldrich) (4 g, 20 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 3 h. Aqueous saturated NH4C1 solution was added to quench the reaction.
The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran.
The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;20, 1;10) to give 2-(1-cyclopropy1-1-methyl-ethyl)-malonic acid diethyl ester as a colorless oil (4.3 g, 89%).
Step B
To a solution of 2-(1-cyclopropy1-1-methyl-ethyl)-malonic acid diethyl ester (4.3 g, 17.8 mmol) in DMSO (30 mL) was added LiC1 (1.5 g, 35.6 mmol) and H20 (0.3 mL, 17.8 mmol).
The reaction mixture was heated at 170 C for 4 h, then poured into a ice-water, extracted with ethyl acetate. The organic layer were separated, washed with water, brine, dried over MgSO4, and concentrated to give 3-cyclopropy1-3-methyl-butyric acid ethyl ester as a colorless oil (2 g, 66%).
Step C
To a solution of 3-cyclopropy1-3-methyl-butyric acid ethyl ester (2 g, 11.75 mmol) in anhydrous tetrahydrofuran (40 mL) at 0 C was added a tetrhydrofuran solution (1 M) of LiA1H4 (23.5 mL, 23.5 mmol) under nitrogen. The reaction mixture was stirred at 0 C for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes = 1;10, 1:5) to give 3-cyclopropy1-3-methyl-butan-1-ol as a colorless oil (0.7 g, 46%).
Step D
To a solution of oxalyl chloride (0.75 g, 5.9 mmol) (Aldrich) in dichloromethane (30 mL) at -78 C was added the solution of dimethyl sulfoxide (0.84 mL, 11.8 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 3-cyclopropy1-3-methyl-butan-l-ol (0.69 g, 5.4 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (2.7 mL, 19.4 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3-cyclopropy1-3-methyl-butyraldehyde as a light yellow oil (Yield: 0.68 g, 98%).
Step E
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted vi.h 3-cyclopropy1-3-methyl-butyraldehyde (0.68 g, 5.3 F311nol) in CH2C12 at room temperature for 5 h to give [3-cyclopropy1-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.9 g, 75%).
Example 99b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropy1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid methyl ester CI F n ,ye = NH
\\
CI F N
M. W. 507.41 C26H26C12F2N202 To a solution of [3-cyclopropy1-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 99a (0.9 g, 3.76 mmol) and (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (1.16 g, 3.76 mmol) prepared in Example 52a in dichloromethane (100 mL) were added triethylamine (0.76 g, 7.5 mmol) and AgF (0.47 g, 3.76 mmol), in one portion. The mixture was stirred at room temperature for overnight. The mixture was then quenched with sat. NH4C1 and extracted with CH2C12. The organic phase was separated, filtered through celite and dried over Na2SO4, and concentrated. The residue was dissolved into methanol (40 mL), and DBU (3 mL) was added. The mixture was heated at 100 C
for 5 h, then cooled to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer were separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes = 1;5, 1:3) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropyl-2-methyl-propy1)-pyrrolidine-2-carboxylic acid methyl ester as a white foam (0.95 g, 50%).
Example 99c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropy1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid CI F OH
Oe=
410' NH
*I"
CI F N
M. W. 493.39 C25H24C12F2N202 To rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropy1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid methyl ester prepared in Example 99b (0.95 g, 1.87 mmol) in tetrahydrofuran (40 mL) was added an aqueous solution (20 mL) of NaOH (0.15 g, 3.7mmol) and methanol (20 mL). The reaction mixture was stirred at room temperature for 18 h. The "pH" of the mixture was adjusted to 5 by aqueous HC1 solution. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, concentrated, and trituated with dichloromethane and hexanes to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid as a white solid (0.78 g, 80%) Example 99d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropy1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI F OH
NH OH
CI \µI\I
M. W. 580.51 C29H33C12F2N303 In a manner similar to the method described in Examples 42e and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropyl-2-methyl-propy1)-pyrrolidine-2-carboxylic acid prepared in Example 99c (0.41 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.43 mL, 2.5 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropy1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.33 g, 70%).
FIRMS (ES )1111Z Cal for C29H33C12F2N303 1 RIM j: 580.1940, found: 580. i 936.
Example 99e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropyl-2-methyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH OH
1101P'Ippr CI
M. W. 580.51 C29H33C12F2N303 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.3 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropyl-2-methyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.11 g, 37%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-cyclopropy1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.11 g, 37%).
HRMS (ES') rniz Calcd for C29H33Cl2F2N303+ H [(M+H)+1: 580.1940, found:
580.1941.
Example 100a Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-3-methyl-pheny1)-acrylonitrile CI
F
CI N
M. W. 306.17 C16H10C12FN
Step A
In a manner similar to the method described in Example 57 Step A, 4-chloro-2-methylbenzyl alcohol (PLATTE) (1.69 g, 11 mmol) was reacted with thionyl chloride (20 mL) to give 4-chloro-2-methylbenzyl chloride as a colorless oil (1.83 g, 97%).
Step B
In a manner similar to the method described in Example 57 Step B, 4-chloro-2-methylbenzyl chloride (1.83 g, 10 mmol) was reacted with KCN (1.76 g, 27 mmol) in ethanol (13 mL) and water (10 mL) at 100 C for 1 h to give 4-chloro-2-methylbenzyl cyanide as a yellow oil (1.2 g, 69%) Step C
In a manner similar to the method described in Example lb, 4-chloro-2-methylbenzyl cyanide (1.2 g, 7.2 mmol) was reacted lyvith 3-chloro-2-fluorobenzaldehyde (1.38 g, 8.7 mmol), methanolic solution (25 wt%) of sodium methoxide (1.82 mL, 8 mmol) in methanol (50 mL) at 50 C for 3 h to give (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-3-methyl-pheny1)-acrylonitrile as a white solid (2.0 g, 91%).
Example 100b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-3-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F oe0-2( NH
1101 µµ
Cl M. W. 519.49 C28H33C12N202 To a solution of [3-cyclopropy1-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (0.93 g, 7.3 mmol) and To a solution of [3-cyclopropy1-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 99a (1.6 g, 7.3 mmol) and (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.5 g, 4.9 mmol) prepared in Example 100a in dichloromethane (100 mL) were added triethylamine (1.7 g, 12 mmol) and AgF (0.9 g, 7.3mmol), in one portion. The mixture was stirred at room temperature for 18 h. The mixture was then quenched with sat. NH4C1 and extracted with CH2C12. The organic phase was separated, filtered through celite and dried over Na2SO4, and concentrated.
The residue was dissolved into tert-butanol (30 mL), and DBU (5 mL) was added.
The mixture was heated at 100 C for 18 h, then cooled to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer were separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes = 1;10, 1:5) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-3-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2 g, 80%).
Example 100c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-3-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F n OH
= NH F.4 OH
CI
M. W. 463.38 C24H25C12FN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-3-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 100b (2.0 g, 3.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-3-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.88 g, 85%).
Example 100d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-3-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide = NH OH
CI
M. W. 550.50 C281434C12FN303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-3-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 100c (0.44 g, 0.76 mmol) was reacted wi(lt 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.33 g, 2.3 mmol), HATU
(0.52 g, 1.37 mmol) and iPr2NEt (0.66 mL, 3.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-3-methyl-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.26 g, 64%).
HRMS (ES-) mlz Calcd for C281-13402FN303+ H M+FIYI: 550.2034, found: 550.2034.
Example 101a Preparation of intermediate [2-(tetrahydro-pyran-4-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester N
I
M. W. 241.33 C13H23NO3 In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with (tetrahydro-pyran-4-y1)-acetaldehyde (Pharrnacore) (0.64 g, 5 minol) in CH2C12 at room temperature for 5 h to give [2-(tetrahydro-pyran-4-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.43 g, 33%).
Example 101b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F 00-1( = - NH o 101"µµ
CI FN
M. W. 551.47 C28H30C12F2N203 In a manner similar to the method described in Example 100b, [2-(tetrahydro-pyran-4-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 100a (0.43 g, 1.8 mmol) was reacted µ;µ,ii.1/ (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (0.31 g, 1 mmol) prepared in Example 52a, AgF (0.19 g, 1.5 mmol), and triethylamine (0.46 g, 4.5 mmol) in dichloromethane (50 mL) at room temperature for 18 h, followed by reaction with DBU in tert-butanol at 100 C for 8 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (0.45 g, 82%).
Example 101e Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
NH o CI FN
M. W. 495.36 C24H22C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 101b (0.45 g, 0.81 mmol) was reacied with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.4 g, 80%).
Example 101d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH OH
1101P' CI
M. W. 582.47 C281-131C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 101c (0.15 g, 0.25 mmol) was reacted ,vvith 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.11 g, 0.74 mmol), HATU (0.17 g, 0.44 mmol) and iPr2NEt (0.21 mL, 1.2 mmol) in CH2C12 at room temperature for h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as 15 a white solid (0.25 g, 80%).
HRMS (ES-) mlz Calcd for C281-131 Cl2F2N304-:- H [( M+1-1)1: 582.1733, found:
582.1731.
Example 102a Preparation of intermediate [2-(1-methyl-cyclohexyl)-eth-(E)-ylideneamino]-acetic acid tert-20 butyl ester I q0 M. W. 253.39 C151-127NO2 Step A.
To a suspension ofNaH (60%, 3 g, 74 mmol) in DME (100 mL) was added methyl (dimethoxyphosphonyl)acetate (Aldrich) (11.3 g, 61.8 mmol). The mixture was stirred at room temperature for 40 min, then cyclohexanone (6.07 g, 61.8 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. Aqueous saturated NH4C1 solution was added and the mixture was extracted with ethyl acetate twice. The organic layers were combined, dried over MgSO4, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;10) to give cyclohexylidene-acetic acid methyl ester as a colorless oil (6.4 g, 67%).
Similar transformation was reported by Bruckner, R. et al in Eur. J. Org.
Chem. 2006, 2119-2133 and the described procedures were used without modification.
Step B
To a suspension of CuI (7.61 g, 40 mmol) in anhydrous ethyl ether (20 mL) at 0 C was added an ethyl ether solution (1.6 M) of MeLi (50 mL, 80 mmol) The reaction mixture was stirred at 0 C for 10 min. The solvent was evaporated under reduced pressure, then dichloromethane (20 mL) was added under nitrogen at 0 C. The mixture was stirred for 5 min. The solvent was evaporated again. To the residue was added dichlormethane (20 mL), and the temperature of the mixture was lowered to -78 C. To the mixture was added chlorotrimethylsilane (4.3 g, 40 mmol) and a dichloromethane solution (20 mL) of cyclohexylidene-acetic acid methyl ester (3.1 g, 20 mmol). The reaction mixture was allowed to slowly warmed to 0 C and stirred for 1 h. Aqueous saturated NH4C1 solution was added to quench the reaction. The mixture was extracted with ethyl ether twice. The organic layers were combined, dried over MgSO4, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;5) to give (1-methyl-cyclohexyl)-acetic acid methyl ester as a colorless oil (3.3 g, 97%).
Similar transformation was reported by Yamamoto, Y. et al in Tetrahedron Letter 44 (2003), 4265-4266 and the described procedures were used without modification.
Step C
To a solution of (1-methyl-cyclohexyl)-acetic acid methyl ester (3.3 g, 19.4 mmol) in anhydrous tetrahydrofuran (50 mL) at 0 C was added a tetrhydrofuran solution (1 M) of LiA1H4 (29 mL, 29 mmol) under nitrogen. The reaction mixture was stirred at 0 C for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated.
The residue was purified by chromatography (Et0Ac:hexanes = 1:4) to give 2-(1-methyl-cyclohexyl)-ethano1 as a colorless oil (2.2 g, 80%).
Step fl To a solution of oxalyl chloride (2.18 g, 17.2 mmol) (Aldrich) in dichloromethane (12 mL) at -78 C was added the solution of dimethyl sulfoxide (2.44 mL, 34.3 mmol) in dichloromethane (8 mL) dropwise. After 5 mins, the solution of 2-(1-methyl-cyclohexyl)-ethanol (2.2 g, 15.6 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (7.8 mL, 56mmo1) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give (1-methyl-cyclohexyl)-acetaldehyde as a light yellow oil (Yield: 2 g, 91%).
Step E
In a manner similar to the method described in Example la, glycine tert-butyl ester (1.87 g, 14.3 mmol) was reacted with (1-methyl-cyclohexyl)-acetaldehyde (2.9 g, 14.3 ram I) in CH2C12 at room temperature for 18 h to give [2-(1-methyl-cyclohexyl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (3.4 g, 95%).
Example 102b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
= NH II
`µm M. W. 563.52 C30H34C12F2N202 In a manner similar to the method described in Example 100b, [2-(1-methyl-cyclohexyl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 101a (2.55 g, 10 mmol) was reacted µ.;vitl/ (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 52a, AgF (1.55 g, 12.3 mmol), and triethylamine (2.8 mL, 20 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (10 ml) in tert-butanol (50 mL) at 100 C for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow solid (3 g, 66%).
Example 102c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F OH
F
41' NH /10 µ`N
FOH
CI F ¨
M. W. 507.41 C26H26C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 102b (3 g, 5.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (3.3 g, 100%).
Example 102d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
OH
NH it lOr CI
M. W. 594.53 C30H35C12F2N303 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 102c (0.5 g, 0.8 mmol) was reacted ,vvith 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.35 g, 2.41 mmol), HATU (0.55 g, 1.45 mmol) and iPr2NEt (0.70 mL, 4.0 mmol) in CH2C12 at room temperature for h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a 15 white solid (0.22 g, 46%).
HRMS (ES-) miz Caled for C301-13502F2N303,- H[( M+1-1)]: 594.2097, found:
594.2094.
Example 102e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-20 cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH ik CI F N
M. W. 594.53 C30H35C12F2N303 Rac-(2R,3S,4R,5S)- 3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.18 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (78 mg, 71%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (80 mg, 73%).
FIRMS (IS) raiz Cala for C301-13502F2N303 ' II [0,11 I-1 )' j: 594.2097, found: 594:2094.
Example 103a Preparation of intermediate 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid benzyl ester j<ii, 0 el M. W. 333.43 C19H27N04 Step A
A mixture of 2,2-dimethylbutyrolactone (6.84 g, 60 mmol) and KOH (3.36 mmol) in H20 (60 mL) was heated at reflux for 2 h. The solution was cooled to room temperature and concentrated to dryness to give 4-hydroxy-2,2-dimethyl-butanoic acid monopotassium salt as a white solid (10.2 g, 100%).
Step B
To the mixture of 4-hydroxy-2,2-dimethyl-butanoic acid monopotassium salt (60 mmol) and benzyl bromide (8.55 mL, 72 mmol) were added NaI (10.8 g, 72 mmol) and K2CO3 (8.29 g, 60 mmol). The reaction mixture was stirred at reflux for 18 h. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by flash column chromatography (Et0Ac:
hexanes=1:2) to give 4-hydroxy-2,2-dimethyl-butyric acid benzyl ester as a colorless oil (9 g, 67%) The same transformations were reported in EP246529 and the described procedures were used without modification.
Step C
To a solution of oxalyl chloride (2.8 mL, 22 mmol) (Aldrich) in dichloromethane (40 mL) at -78 C was added the solution of dimethyl sulfoxide (3.1 mL, 44 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 4-hydroxy-2,2-dimethyl-butyric acid benzyl ester (4.5 g, 20 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (10 mL, 72 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 2,2-dimethy1-4-oxo-butyric acid benzyl ester as a colorless oil (Yield: 2.9 g, 66%).
Step D
In a manner similar to the method described in Example la, glycine tert-butyl ester (1.72 g, 13.2 mmol) was reacted with 2,2-dimethy1-4-oxo-butyric acid benzyl ester (4.1 g, 13.2 inmol) in CH2C12 at room temperature for 18 h to give 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid benzyl ester as a colorless oil (4.1 g, 93%).
Example 103b Preparation of intermediate rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
=NH
Cl 0 01 F N
M. W. 643.56 C34H34C12F2N204 In a manner similar to the method described in Example 100b, 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid benzyl ester prepared in Example 103a (4.1 g, 12.3 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 52a, AgF (1.55 g, 12.3 mmol), and triethylamine (2.5 g, 24 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (4 ml) in tert-butanol (40 mL) at 100 C for 4 h to give rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow gum (0.98 g, 19%).
Example 103c Preparation of intermediate rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid Fj OH
CI F of0H
NH
110"P0 Cl F N
M. W. 587.46 C30H2602F2N204.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 103b (0.98 g, 1.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white gum (0.94 g, 86%).
Example 103d Preparation of rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F n OH
NH
1101 F 0 *
M. W. 674.57 C34H35C12F2N305 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 103c (0.94 g, 1.34 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.58 g, 4.0 mmol), HATU (0.92 g, 2.41 mmol) and iPr2NEt (1.17 mL, 6.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbony1-2-methyl-propy1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.2 g, 22%).
[IRAS (ES') raiz Cacd for C34H35C12F2N305, 11 [( Mi ]: 074.1995, fbund:
674.1991.
Example 104a Preparation of intermediate 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid methyl ester M. W. 257.33 C13H23N04 Step A
A mixture of 2,2-dimethylbutyrolactone (6.84 g, 60 mmol) and KOH (3.36 g) in H20 (60 mL) was heated at reflux for 2 h. The solution was cooled to room temperature, and acidified to "pH"
5 with aqueous HC1 solution. The mixture was then extracted with ethyl acetate three times. The combined organic layers wer washed with brine, dried over MgSO4, concentrated under reduced pressure to give 4-hydroxy-2,2-dimethyl-butanoic acid as a colorless oil (4 g, 51%).
Step B
To the mixture of 4-hydroxy-2,2-dimethyl-butanoic acid (2.2 g, 16.6 mmol) in ethyl ether (16 mL) and methanol (24 mL) at 0 C was added a hexane solution (2.0 M) of trimethylsilyldiazomethane (Aldrich) (12.5 mL, 25mmo1). The reaction mixture was stirred at 0 C for 1 h. The solvents were evaporated. The residue was taken up in ethyl acetate, washed with diluted aqueous HC1 solution, saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give 4-hydroxy-2,2-dimethyl-butyric acid methyl ester as a colorless oil (1.5 g, 62%).
Step C
To a solution of oxalyl chloride (1.09 mL, 12.5 mmol) (Aldrich) in dichloromethane (20 mL) at -78 C was added the solution of dimethyl sulfoxide (1.77 mL, 25 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 4-hydroxy-2,2-dimethyl-butyric acid methyl ester (1.5 g, 11.3 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (5.7 mL, 41 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min.
Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 2,2-dimethy1-4-oxo-butyric acid methyl ester as a light yellow oil (Yield: 1.2 g, 81%).
Step D
In a manner similar to the method described in Example la, glycine tert-butyl ester (1.09 g, 8.32 mmol) was reacted with 2,2-dimethy1-4-oxo-butyric acid methyl ester (1.2 g, 8.32 11111101) in CH2C12 at room temperature for 18 h to give 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid methyl ester as a colorless oil (2.1 g, 100%).
Example 104b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methoxycarbony1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI
NH
'Js.
N,µ
Cl FN 0 M. W. 567.47 C281-130C12F2N204 In a manner similar to the method described in Example 100b, 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid methyl ester prepared in Example 104a (2.1 g, 8.3 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (2.05 g, 6.7 mmol) prepared in Example 52a, AgF (1.27 g, 10 mmol), and triethylamine (2.3 mL, 17 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (2 ml) in tert-butanol (10 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methoxycarbony1-2-methyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (0.75 g, 20%).
Example 104c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
= NH
F.LOH
0, CI [10 N 0 M. W. 511.36 C24H22C12F2N204.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 104b (0.7 g, 1.23 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.75 g, 97%).
Example 104d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NHOH
1101 µ \\N 0 0.
CI
M. W. 598.47 C28H31C12F2N305 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenoxycarbonyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 104c (0.75 g, 1.26 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.52 g, 3.6 mmol), HATU (0.82 g, 2.16 mmol) and iPr2NEt (1.04 mL, 6 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-methyl-2-phenoxycarbonyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.45 g, 56%).
FIRMS (ES ') rwrz Ca'cc' for C28H31C12F2N305-,- H [(M+H )1: 598.1682, found:
598.1679.
Example 105a Preparation of intermediate [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester oo an /
M. W. 343.59 C18H37NO3Si Step A
A mixture of 2,2-dimethyl-propane-1,3-diol (Aldrich) (10 g, 96 mmol) and imidazole (9.8 g, 140 mmol) in dichloromethane (200 mL) was added tert-butyldimethylchlorosilane (15.9 g, 10.6 mmol). The reactiom mixture was stirred at room temperature for 0.5 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with dichloromethane. The combined organic layers wer washed with brine, dried over MgSO4, concentrated to give 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propan-1-ol as a colorless oil (20.4 g, 97%).
Step B
To the solution of 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propan-1-ol (20.4 g, 93 mmol) and triethylamine (26 g, 186 mmol) in dichloromethane (200 mL) at 0 C
was added a dichlormethane solution (20 mL) of methanesulfonyl chloride (Aldrich) (8.69 mL, 112 mmol).
The reaction mixture was stirred at 0 C for 2 h. Water was added. Organic layer was separated, the aqueous layer was extracted with dichlormethane. The combined organic layers were washed with diluted aqueous HC1 solution, saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give methanesulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propyl ester as a yellow oil (24 g, 87%).
Step C
To the solution of methanesulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propyl ester (5 g, 16.8 mmol) in anhydrous dimethyl sulfoxide (50 mL) was added KCN
(2.85 g, 44 mmol). The reaction mixture was heated at 120 C for 16 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes = 1;4) to give 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyronitrile as a yellow oil (2.2 g, 57%).
Step D
To a solution of 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyronitrile (2.2 g, 9.67 mmol) (Aldrich) in dichloromethane (20 mL) at -78 C was added a toluene solution (1 M) of DIBAL
(10.6 mL, 10.6 mmol) dropwise. The reaction mixture was stirred at 0 C for 3 h. The mixture was poured into aqueous saturated NH4C1 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1:4) to give 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyraldehyde as a colorless oil (Yield: 0.84 g, 38%).
Step E
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.52 g, 3.64 mmol) was reacted wih 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyraldehyde (0.84 g, 3.64 mmol) in CH2C12 at room temperature for 18 h to give [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.25 g, 100%).
Example 105b Preparation of intermediate rac-(2R,3S,4R,5S)-5-[3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
NH
1101 µ`Ni M. W. 653.72 C33H44C12F2N203Si In a manner similar to the method described in Example 100b, [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 105a (1.25 g, 3.64 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (0.93 g, 3 mmol) prepared in Example 52a, AgF
(0.57 g, 4.5 mmol), and triethylamine (1.05 mL, 7.5 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (3.6 ml) in tert-butanol (15 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-5-[3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (1.2 g, 61%).
Example 105c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F 0.e0H
NH
F
OH
110 `µki CI F
M. W. 483.35 C23H22C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-543-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 105b (1.1g, 1.68 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 100%).
Example 105d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide NH OH
1101P'OH
CI
M. W. 570.46 C27H31C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 105c (1 g, 1.67 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.73 g, 5 mmol), HATU (1.14 g, 3 mmol) and iPr2NEt (1.46 mL, 8.4 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.3 g, 64%).
HRMS (ES') MIZ Calcd for C27H31 Cl2F2N304 H [(M+H)1: 570.1733, found:
570.1731.
Example 105e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
= NHOH
1101 µOH
CI
M. W. 570.46 C27H31C12F2N304 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.24 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (102 mg, 43%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (93 mg, 39%).
FIRMS (ES ITIPZ Caled for C27H31 Cl2F2N304 II [GNI-WY]: 570.173:3, found:
570.1730, Example 106a Preparation of intermediate [3,3-diethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester 00y-Nk M. W. 255.40 C15H29NO2 Step A
To a solution of dimethyl malonate (10 g, 75mmol), 3-pentanone (6.5 g, 75 mmol) and pyridine (7.9 g, 100 mmol) in anhydrous tetrahydrofuran (300 mL) at 0 C was added a dichloromethane solution (1 M) of TiC14 (100 mL, 100 mmol) during a period of 1 h. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 18 h.
Water was added to quench the reaction. The mixture was extracted with ethyl ether. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate.
The organic layers were combined, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;20) to give 2-(1-ethyl-propylidene)-malonic acid dimethyl ester as a light yellow oil (7 g, 46%).
Step B
To a suspension of Cul (7.61 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) at -50 C was added ethylmagnesium chloride (2 M, 40 mL, 80 mmol) during a period of 15 min.
After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to -50 C, a tetrahydrofuran solution (50 mL) of 2-(1-ethyl-propylidene)-malonic acid dimethyl ester (3.5 g, 17.5 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 3 h. Aqueous saturated NH4C1 solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;30) to give 2-(1,1-diethyl-propy1)-malonic acid dimethyl ester as a colorless oil (2.6 g, 57%).
Step C
To a solution of 2-(1,1-diethyl-propy1)-malonic acid dimethyl ester (2.5 g, 11 mmol) in DMSO
(30 mL) was added LiC1 (0.91 g, 21.6 mmol) and H20 (0.19 mL, 11 mmol). The reaction mixture was heated at 170 C for 4 h, then poured into a ice-water, extracted with ethyl acetate.
The organic layer were separated, washed with water, brine, dried over MgSO4, and concentrated to give 3,3-diethyl-pentanoic acid methyl ester as a yellow oil (1.9 g, 100%).
Step D
To a solution of 3,3-diethyl-pentanoic acid methyl ester (1.9 g, 11 mmol) in anhydrous tetrahydrofuran (50 mL) at 0 C was added a tetrhydrofuran solution (2 M) of LiA1H4 (9 mL, 18 mmol) under nitrogen. The reaction mixture was stirred at 0 C for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated to give 3,3-diethyl-pentan-1-ol as a yellow oil (1.4 g, 90%).
Step E
To a solution of oxalyl chloride (0.86 mL, 9.9 mmol) (Aldrich) in dichloromethane (20 mL) at -78 C was added the solution of dimethyl sulfoxide (1.4 mL, 19.8 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 3,3-diethyl-pentan-l-ol (1.3 g, 9 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (4.5 mL, 32 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3,3-diethyl-pentanal as a yellow oil (Yield: 1 g, 78%).
Step F
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.92 g, 7 mmol) was reticied with 3,3-diethyl-pentanal (I g, 7 J111 nol) in CH2C12 at room temperature for 5 h to give [3,3-diethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.8 g, 100%).
Example 106b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
O2O= : NH
1101"' CI F N
M. W. 507.41 C26H26C12F2N202 In a manner similar to the method described in Example 100b, [3,3-diethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 106a (1.8 g, 7 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.74 g, 5.6 mmol) prepared in Example 52a, AgF (1.1 g, 8.6mmol), and triethylamine (1.95 mL, 14 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (7 ml) in tert-butanol (30 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white gum (1.8 g, 57%).
Example 106c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F 0.e0H
= NH
F.LOH
[10 CI F N
M. W. 509.43 C26H28C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 106b (1.8 g, 3.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a light yellow solid (2 g, 100%).
Example 106d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide NH OH
1101"' CI
M. W. 596.54 C30H37C12F2N303 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 106c (0.5 g, 0.8 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.35 g, 2.4 mmol), HATU (0.55 g, 1.4 mmol) and iPr2NEt (0.7 mL, 4 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.33 g, 70%).
HIS (ES') raiz Cadcd for C301137C12F2N3031 H [( 596,2253, lbund: 596.2254.
Example 107a Preparation of intermediate [3-ethy1-3-methyl-pent-(E)-ylidenea mino]-acetic acid tert-butyl ester I
M. W. 241.38 C14H27NO2 Step A
To a suspension of CuI (5.7 g, 30 mmol) in anhydrous tetrahydrofuran (100 mL) at -50 C was added methylmagnesium chloride (3 M, 20 mL, 60 mmol) during a period of 15 min. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to -50 C, a tetrahydrofuran solution (20 mL) of 2-(1-ethyl-propylidene)-malonic acid dimethyl ester (3 g, 15 mmol) prepared in Example 106a Step A was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 1 h. Aqueous saturated NH4C1 solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;30) to give 2-(1-ethyl-1-methyl-propyl)-malonic acid dimethyl ester as a colorless oil (3 g, 93%).
Step B
To a solution of 2-(1-ethyl-l-methyl-propy1)-malonic acid dimethyl ester (3 g, 14 mmol) in DMSO (30 mL) was added LiC1 (1.2 g, 28 mmol) and H20 (0.25 mL, 14 mmol). The reaction mixture was heated at 170 C for 3 h, then poured into a ice-water, extracted with ethyl acetate.
The organic layer were separated, washed with water, brine, dried over MgSO4, and concentrated to give 3-ethyl-3-methyl-pentanoic acid methyl ester as a yellow oil (1.5 g, 68%).
Step C
To a solution of 3-ethy1-3-methyl-pentanoic acid methyl ester (1.5 g, 9.4 mmol) in anhydrous tetrahydrofuran (30 mL) at 0 C was added a tetrhydrofuran solution (2 M) of LiA1H4 (5 mL, 10 mmol) under nitrogen. The reaction mixture was stirred at 0 C for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated to give 3-ethy1-3-methyl-pentan-1-ol as a yellow oil (1.3 g, 100%).
Step D
To a solution of oxalyl chloride (0.96 mL, 11 mmol) (Aldrich) in dichloromethane (20 mL) at -78 C was added the solution of dimethyl sulfoxide (1.56 mL, 22 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 3-ethy1-3-methyl-pentan-l-ol (1.3 g, 10 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (5 mL, 36 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3-ethyl-3-methyl-pentanal as a light yellow oil (Yield: 1 g, 78%).
Step F
In a manner similar to the method described in Example la, glycine tert-butyl ester (1.0 g, 7.8 mmol) was reacted with 3-ethyl-3-methyl-pentanal I g, 7,8 trimoi) in CH2C12 at room temperature for 5 h to give [3-ethyl-3-methyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.9 g, 100%).
Example 107b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethy1-2-methyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI
= : NH
CI FN
M. W. 551.51 C29H34C12F2N202 In a manner similar to the method described in Example 100b, [3-ethyl-3-methyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 107a (1.9 g, 7.8 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (1.9 g, 6.2 mmol) prepared in Example 52a, AgF (1.2 g, 9.4 mmol), and triethylamine (2.1 mL, 15 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (7 ml) in tert-butanol (30 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethyl-2-methyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow gum (2.5 g, 74%).
Example 107c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethyl-2-methyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F 0.e0H
F. 110 [101 CI F N
M. W. 495.40 C25H26C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethyl-2-methyl-buty1)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 107b (1.8 g, 3.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethyl-2-methyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a light yellow solid (2.5 g, 91%).
Example 107d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethy1-2-methyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide NH OH
1101P \µ=
CI
M. W. 582.52 C29H35C12F2N303 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethyl-2-methyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 106c (0.6 g, 1 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.43 g, 3 mmol), HATU (0.67 g, 1.8 mmol) and iPr2NEt (0.86 mL, 4.9 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethyl-2-methyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.3 g, 53%).
FIRMS (ES-) m/z Caled for C29H35C12F2N303 II [0,1111)' j: 582.2097, found:
582.2096, Example 108a Preparation of intermediate (Z)-2-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-2-fluoro-pheny1)-acrylonitrile CI
F
401 -1\1 CI
M. W. 328.12 C15H6C12F3N
Step A
To the solution of 4-chloro-2,6-difluorobenzyl bromide (Alfa) (2.5 g, 10 mmol) in ethanol (13 mL) and H20 (10 mL) was added KCN (1.75 g, 27 mmol). The reaction mixture was heated at 100 C for 1 h. The mixture was cooled, and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes = 1;4) to give (4-chloro-2,6-difluoro-pheny1)-acetonitrile as a yellow oil (1.1 g, 57%).
Step B
In a manner similar to the method described in Example lb, (4-chloro-2,6-difluoro-pheny1)-acetonitrile (1.1 g, 6 mmol) was reacted with 2-fluoro-3-chlorobenzaldehyde (1.2 g, 7mmol), methanolic solution (25 wt%) of sodium methoxide (1.5 mL, 7 mmol) in methanol (40 mL) at 50 C for 3 h to give (Z)-2-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-2-fluoro-pheny1)-acrylonitrile as a white solid (1.5 g, 75%).
Example 108b Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI 1c,(0?c/
410' NH
F
CI 111' F N
M. W. 505.46 C27H31C12FN202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (1 g, 5 mmol) was reacted with (Z)-2-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-2-fluoro-pheny1)-acrylonitrile (1.3 g, 4mmo1) prepared in Example 109a, AgF (0.77 g, 6 mmol), and triethylamine (1.4 mL, 10 mmol) in dichloromethane (120 mL) at room temperature for 18 h, followed by the reaction with DBU
(4.8 ml) in tert-butanol (20 mL) at 100 C for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white gum (0.9 g, 41%).
Example 108c Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI 0,0H
= NH
F ralõõ
W
Cl 11WP F
M. W. 467.35 C23H22C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 108b (0.9 g, 1.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.9 g, 91%).
Example 108d Preparation of rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
NHOH
\\N
M. W. 572.45 C27H30C12F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 108c (0.4 g, 0.67 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.29 g, 2 mmol), HATU
(0.46 g, 1.2 mmol) and iPr2NEt (0.58 mL, 3.3 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 77%).
HIS (ES-) mlz Cated for C27H3002F2N303,-- H[( M+1-1)1: 572.1689, found:
572.1691.
Example 109a Preparation of intermediate (Z)-2-(4-chloro-2,5-difluoro-pheny1)-3-(3-chloro-2-fluoro-pheny1)-acrylonitrile CI
F
N
:
M. W. 328.12 C15H6C12F3N
Step A
To the solution of 4-chloro-2,5-difluorobenzoic acid (Oakwood) (6.08 g, 31 mmol) in anhydrous tetrahydrofuran (75 mL) at 0 C was added a solution of BH3.THF (1 M, 62 mL, 62 mmol). The reaction mixture was stirred at room temperature for 18 h. Aqueous HC1 solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give (4-chloro-2,5-difluoro-pheny1)-methanol as a colorless oil (5.5 g, 98%).
Step B
A mixture of (4-chloro-2,5-difluoro-pheny1)-methanol (5.5 g, 32 mmol) in thionyl chloride (25 mL) was heated at refluxing (100 C) for 30 min. The mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous NaHCO3 solution, water, brine, dried over MgSO4, and concentrated to give 1-chloro-4-chloromethy1-2,5-difluoro-benzene as a yellow oil (2.1 g, 34%).
Step C
To the solution of 1-chloro-4-chloromethy1-2,5-difluoro-benzene (2.1 g, 11 mmol) in ethanol (13 mL) and H20 (10 mL) was added KCN (1.8 g, 28 mmol). The reaction mixture was heated at 100 C for 1 h. The mixture was cooled, and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Achexanes = 1;4) to give 4-chloro-2,5-difluoro-pheny1)-acetonitrile as a light yellow oil (1.0 g, 50%).
Step fl In a manner similar to the method described in Example lb, 4-chloro-2,5-difluoro-phenyl)-acetonitrile (1.0 g, 5 mmol) was reacted with 2-fluoro-3-ch1orobenza1dehyde (1.0 g, 6 mmol), methanolic solution (25 wt%) of sodium methoxide (1.3 mL, 5.9 mmol) in methanol (40 mL) at 50 C for 3 h to give (Z)-2-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-acrylonitrile as a white solid (1.3 g, 75%).
Example 109b Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-pheny1)-3-(3-ehloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI 1c,e0K
NH
F
Cl M. W. 505.46 C27H31C12FN202 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (5 mmol) was reacted with give (Z)-2-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-2-fluoro-pheny1)-acrylonitrile (1.3 g, 3 mmol) prepared in Example 109a, AgF (0.77 g, 6 mmol), and triethylamine (1.4 mL, 10 mmol) in dichloromethane (120 mL) at room temperature for 18 h, followed by the reaction with DBU
(4.8 ml) in tert-butanol (20 mL) at 100 C for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylie acid tert-butyl ester as a light yellow gum (1.5 g, 69%).
Example 109c Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI
= NH FFOH
F "
M. W. 467.35 C23H22C12F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 109b (1.5 g, 2.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (1.5 g, 91%).
Example 109d Preparation of rac-(2R,3R,4R,5 S)-4-(4-chloro-2,5-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI
= NHOH
F
F
CI
M. W. 572.45 C27H30C12F2N303 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 108c (0.5 g, 0.84 mmol) was reaeLed with 24(S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.73 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-pheny1)-3-(3-chloro-pheny1)-4-cyano-5-(2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 50%).
FIRMS (ES') rcilz Calcd fi,r C27H30C12F2N3034 H [( M-i- II)]: 572.1689, thund:
572.1689.
Example 110a Preparation of intermediate [4-methoxy-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester 00y-N
1 o*.
M. W. 243.35 C13H25NO3 Step A.
A mixture of 2,2-dimethyl-propane-1,3-diol (Aldrich) (5 g, 48 mmol) in anhydrous ethyl ether (100 mL) at 0 C was added thionyl chloride (8.7 mL, 120 mmol). The reactiom mixture was stirred at 0 C for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl ether. The combined organic layers wer washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, concentrated to give 5,5-dimethyl-[1,3,2]dioxathiane 2-oxide as a light pink oil (4.8 g, 82%).
Step B
To the solution of 5,5-dimethyl-[1,3,2]dioxathiane 2-oxide (4.8 g, 39 mmol) in anhydrous dimethyl sulfoxide (50 mL) was added NaCN (5.8 g, 118 mmol). The reaction mixture was heated at 120 C for 5 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes = 1;4) to give 4-hydroxy-3,3-dimethyl-butyronitrile as a yellow oil (1.6 g, 38%).
Step C
To the solution of 4-hydroxy-3,3-dimethyl-butyronitrile (0.8 g, 7 mmol) in anhydrous dimethylformamide (5 mL) was added NaH (60%, 0.42 g, 11 mmol). The mixture was stirred at room temperature for 15 min, then iodomethane (0.88 mL, 14 mmol) was added.
The mixture was stiired at room temperature for 1 h. Water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, and concentrated to give 4-methoxy-3,3-dimethyl-butyronitrile as a yellow oil (0.85 g, 94%).
Step fl To a solution of 4-methoxy-3,3-dimethyl-butyronitrile (0.85 g, 6.7 mmol) in dichloromethane (20 mL) at -78 C was added a toluene solution (1 M) of DIBAL (7.4 mL, 7.4 mmol) dropwise.
The reaction mixture was stirred at 0 C for 1 h. The mixture was poured into aqueous saturated NH4C1 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to give 4-methoxy-3,3-dimethyl-butyraldehyde as a colorless oil (Yield: 0.3 g, 34%).
Step E
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.3 g, 2.3 mmol) was reacted with 4-methoxy-3,3-dimethyl-butyraldehyde (0.3 g, 2.3 1 nol) in CH2C12 at room temperature for 18 h to give [4-methoxy-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.56 g, 100%).
Example 110b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
NH
1101""
CI F N
M. W. 553.48 C28H32C12F2N203 In a manner similar to the method described in Example 100b, [4-methoxy-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 110a (3.8 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (0.94 g, 3 mmol) prepared in Example 52a, AgF (0.58 g, 4.6 mmol), and triethylamine (1.06 mL, 7.6 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (3.6 ml) in tert-butanol (20 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow solid (1 g, 59%).
Example 110c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
= NH FOH
F. 11 [10 CI F N
M. W. 497.37 C24H24C12F21\1203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 105b (1.0 g, 1.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (0.9 g, 82%).
Example 110d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NHOH
1101 µ0 \\
CI F
N
M. W. 584.49 C28I-133C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 110c (0.45 g, 0.74 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.32 g, 2.2 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (0.64 mL, 3.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.28 g, 65%).
FIRMS (ES-) rwrz Calcd for C281-133C12F2N304* H [(M+H )1: 584.1889, found:
584.1 X9O.
Example 110e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH OH
1101P'0 CI
M. W. 584.49 C281-133C12F2N304 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.24 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (114 mg, 48%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methoxy-2,2-dimethyl-propy1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (114 mg, 48%).
FIRMS (ES-) ITI/Z Calcd for C281-133C12F2N304* H [(M+H )1: 584.1889, found:
584.1892.
Example 111a Preparation of intermediate 3-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester OO) I
a /
M. W. 371.64 C201--141NO3Si Step A
A mixture of 2,2-diethyl-propane-1,3-diol (Aldrich) (5.5 g, 40 mmo1) in anhydrous ethyl ether (100 mL) at 0 C was added thionyl chloride (10.6 g, 90 mmol). The reactiom mixture was stirred at 0 C for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl ether. The combined organic layers wer washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, concentrated to give 5,5-diethyl41,3,2]dioxathiane 2-oxide as a colorless oil (7 g, 98%).
Step B
To the solution of 5,5-diethyl-[1,3,2]dioxathiane 2-oxide (7 g, 39 mmol) in anhydrous dimethyl sulfoxide (40 mL) was added NaCN (3.9 g, 80mmol). The reaction mixture was heated at 120 C
for 20 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes = 1;2) to give 3-ethyl-3-hydroxymethyl-pentanenitrile as a yellow oil (1.7 g, 31%).
Step C
To the solution of 3-ethy1-3-hydroxymethyl-pentanenitrile (1.7 g, 12 mmol) and imidazole (1.2 g, 18 mmol) in dichloromethane (80 mL) was added tert-butyldimethylchlorosilane (2 g, 13 mmol).
The reactiom mixture was stirred at room temperature for 2 h. Water was added.
The organic layer was separated, the aqueous layer was then extracted with dichloromethane. The combined organic layers wer washed with brine, dried over MgSO4, concentrated to give 3-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-pentanenitrile as a colorless oil (2.28 g, 74%).
Step D
To a solution of 3-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-pentanenitrile (2.28 g, 8.9 mmol) in dichloromethane (20 mL) at -78 C was added a toluene solution (1 M) of DIBAL (9.8 mL, 9.8 mmol) dropwise. The reaction mixture was stirred at 0 C for 1 h. The mixture was poured into aqueous saturated NH4C1 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to give 3-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-pentanal as a colorless oil (Yield: 1.5 g, 65%).
Step E
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.78 g, 5.8 mmol) was reacted with 3-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-pentanal (1 .5 g, 5.8 mrnol) in CH2C12 at room temperature for 18 h to give [4-methoxy-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.2 g, 100%).
Example 111b Preparation of intermediate rac-(2R,3S,4R,5S)-5-[2-(tert-butyl-dimethyl-silanyloxymethyl)-2-ethyl-buty1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
= NH
Cl F N
--f-M. W. 681.77 C35H48C12F2N203Si In a manner similar to the method described in Example 100b, give [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 111a (2.2 g, 5.8 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.43 g, 4.6 mmol) prepared in Example 52a, AgF (0.89 g, 7 mmol), and triethylamine (1.6 mL, 12 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (7 ml) in tert-butanol (20 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-5-[2-(tert-butyl-dimethyl-silanyloxymethyl)-2-ethyl-buty1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow solid (1.8 g, 58%).
Example 111e Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethy1-2-hydroxymethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Ci F \ OH
= NH
u OH
CI F N
M. W. 511.40 C25H26C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-542-(tert-butyl-dimethyl-silanyloxymethyl)-2-ethyl-buty1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 111b (1.8 g, 2.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethyl-2-hydroxymethyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a light yellow solid (1.5 g, 94%).
Example 111d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethy1-2-hydroxymethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH OH
1101P'OH
CI
M. W. 598.51 C29H35C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethyl-2-hydroxymethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 111c (1.1 g, 1.8 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.78 g, 5 mmol), HATU (1.2 g, 3 mmol) and iPr2NEt (1.6 mL, 9 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2-ethy1-2-hydroxymethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.11 g, 10%).
FIRMS (ES') Tri/z (Cacd for C29H35C12F2N304H- H [( H)]: 598.2046, fbund:
598.2045.
Example 112a Preparation of intermediate [2-(3-methyl-oxetan-3-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester 00?
M. W. 227.31 C12H21NO3 Step A
To a solution of 3-methy1-3-oxetanemethano1 (Aldrich) (3.5 g, 34 mmol) and triethylamine (10 g, 103 mmol) in dichloromethane (100 mL) at 0 C was added a dichlormethane solution (20 mL) of methanesulfonyl chloride (Aldrich) (5.08 g, 45 mmol). The reaction mixture was stirred at 0 C for 2 h. Water was added. Organic layer was separated, the aqueous layer was extracted with dichlormethane. The combined organic layers were washed with diluted aqueous HC1 solution, saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give methanesulfonic acid 3-methyl-oxetan-3-ylmethyl ester as a yellow oil (6 g, 97%).
Step B
To the solution of methanesulfonic acid 3-methyl-oxetan-3-ylmethyl ester (6 g, 33 mmol) in anhydrous dimethyl sulfoxide (30 mL) was added NaCN (3.2 g, 67 mmol). The reaction mixture was heated at 130 C for 3 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give (3-methyl-oxetan-3-y1)-acetonitrile as a yellow oil (2.5 g, 68%).
Step C
To a solution of (3-methyl-oxetan-3-y1)-acetonitrile (2.5 g, 22.5 mmol) in dichloromethane (30 mL) at -78 C was added a toluene solution (1 M) of DIBAL (24.7 mL, 24.7 mmol) dropwise.
The reaction mixture was stirred at 0 C for 3 h. The mixture was poured into aqueous saturated NH4C1 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to give (3-methyl-oxetan-3-y1)-acetaldehyde as a colorless oil (Yield: 0.8 g, 31%).
Step D
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.92 g, 7 mmol) was reacted iffi (3-methyl-oxetan-3-y1)-acetaldehyde (0.8 g, 7 J111 non in CH2C12 at room temperature for 18 h to give [2-(3-methyl-oxetan-3-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.6 g, 100%).
35 Example 112b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
-Cl FN
M. W. 537.44 C27H28C12F2N203 In a manner similar to the method described in Example 100b[2-(3-methyl-oxetan-3-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 112a (1.6 g, 7 mmol) was reacted µ;vitl/ (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (1.7 g, 5.6 mmol) prepared in Example 52a, AgF (1.1 g, 8.5 mmol), and triethylamine (1.9 mL, 14 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (6.7 ml) in tert-butanol (20 mL) at 100 C for 2 h to rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow gum (1.0 g, 33%).
Example 112c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Cl F 0.e0H
= NH 0 u OP
Cl FN
M. W. 481.33 C23H20C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 112b (1.0 g, 1.9 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 91%).
Example 112d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI F
NH OH
1101P' \`%
CI FN
M. W. 568.45 C27H29C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 112c (0.5 g, 0.84 mmol) was reacted ,Nith 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU
(0.57 g, 1.5 mmol) and iPr2NEt (0.73 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.23 g, 48%).
HRMS (ES-) miz Calcd for C27H29C12F2N304,-- H[( V1+H)]: 568.1576, found:
568.1579.
Example 113a Preparation of intermediate [2-(3-ethyl-oxetan-3-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester I
M. W. 241.33 C13H23NO3 Step A
In a manner similar to the methods described in Example 112a Step A. Step B., and Step C., 3-ethyl-3-oxetanemethanol (TCI-US) (3.5 g, 30 mmol) was reacted with triethylamine (6.6 g, 60 mmol) and treated with NaCN (2.2 g, 46mmo1) in anhydrous dimethyl sulfoxide at 130 C, followed by the reaction with DIBAL (1 M in heptane, 27 mL, 27 mmol) in dichloromethane at 0 C to give (3-ethyl-oxetan-3-y1)-acetaldehyde as a light yellow oil (Yield: 2.5 g, 26% for three steps).
Step B
In a manner similar to the method described in Example la, glycine tert-butyl ester (1 g, 7.8 mmol) was reacted with (3-ethyl-oxetan-3-y1)-acetaldehyde (1 g, 7.8 mmol) in CH2C12 at room temperature for 18 h to give [2-(3-ethyl-oxetan-3-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (1.9 g, 100%).
Example 113b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester Cl F
= NH 0 CI F N
M. W. 551.41 C28H30C12F2N203 In a manner similar to the method described in Example 100b, [2-(3-ethyl-oxetan-3-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 113a (1.9 g, 7.8 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.9 g, 6.2 mmol) prepared in Example 52a, AgF (1.2 g, 9.5 mmol), and triethylamine (2.2 mL, 16 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (7.5 ml) in tert-butanol (10 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (2 g, 58%).
Example 113c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
= NH 0 F.LOH
[10 CI FN
M. W. 495.36 C24H22C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 113b (2 g, 3.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2 g, 91%).
Example 113d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH OH
OP
CI
M. W. 582.47 C28I-131C12F2N304 In a manner similar to the method described in Examples 42c and 42d rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 105c (1 g, 1.6 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.7 g, 5 mmol), HATU (1.1 g, 3 mmol) and iPr2NEt (1.4 mL, 8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.56 g, 58%).
FIRMS (ES-) rwrz Ca'cc' for C28H31C12F2N304* H [(M+H )]: 582.1733, found:
582.1732.
Example 114a Preparation of intermediate [2-[1-(tert-tutyl-dimethyl-silanyloxymethyl)-cyclopropyl] -eth-(E)-ylideneamino]-acetic acid tert-butyl ester 00y-0 i )4-.
M. W. 341.57 C18H35NO3Si Step A
In a manner similar to the methods described in Example 111a Step A. Step B., Step C., and Step D., 1,1-bis(hydroxymethyl)-cyclopropane (Aldrich) (4 g, 39 mmol) was reacted with thionyl chloride (14 g, 126 mmol) in anhydrous ethyl ether at 0 C, then reacted with NaCN (2.4 g, 49 mmol) in anhydrous dimethyl sulfoxide 120 C for 18 h, then treated with tert-butyldimethylchlorosilane (1.4 g, 9 mmol) and imidazole (0.85 g, 13 mmol) in dichloromethane at room temperature, follone by the reaction with DIBAL (1 M in heptane, 8.3 mL, 8.3 mmol) at 0 C to give [1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopropyl]-acetaldehyde as a colorless oil (Yield: 1.3 g, 15% for four steps).
Step B
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.75 g, 5.7 mmol) was reacted with [1-(tert-butyl-dimethyl-silanyloxym ethyl)-cyclopropyl]-acetaldehyde ( .3 g, 5.7 rimiol) in CH2C12 at room temperature for 18 h to give [2-[1-(tert-tutyl-dimethyl-silanyloxymethyl)-cyclopropyl]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.9 g, 100%).
Example 114b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
= NH
A
OH
Cl FN
M. W. 537.44 C27H28C12F2N203 In a manner similar to the method described in Example 100b, [241-(tert-tutyl-dimethyl-silanyloxymethyl)-cyclopropyl]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 114a (1.9 g, 5.7 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.4 g, 4.6 mmol) prepared in Example 52a, AgF (0.89 g, 7.1 mmol), and triethylamine (1.6 mL, 12 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (5 ml) in tert-butanol (20 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (0.4 g, 30%).
Example 114c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Cl F 0.e0H
= NH
A u OH
Cl FN
M. W. 481.33 C23H20C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 114b (0.4 g, 0.74 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.4 g, 91%).
Example 114d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI F
= NHOH
A
1101 µ
CI FN OH
M. W. 568.45 C27H29C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyp-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 114c (0.4 g, 0.67 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.29 g, 2 mmol), HATU (0.46 g, 1.2 mmol) and iPr2NEt (0.58 mL, 3.4 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.15 g, 40%).
I-IRMS (S) Ca lcd ibr C27H29C12F2N304 4-i1 [(N/P j: 568.1576, fburid: 568.1578.
Example 114e Preparation of (2R,3S,4R,55)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
.NH OH
A
1101 µ
CI FN OH
M. W. 568.45 C27H29C12F2N304 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.12 g) was separated by chiral SFC chromatography to provide chiral (2R,35,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (46 mg, 38%) and chiral (2S,3R,4S,5R)-3-(3-ehloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (48 mg, 40%).
FIRMS (IS) raiz C.'alcd for C27H29C12F2N304 II [0,1 j: 568.1576, fi.)u:
568.1578, Example 115a Preparation of intermediate [2-[1-(tert-tutyl-dimethyl-silanyloxymethyl)-cyclobutyl]-eth-(E)-ylideneamino]-acetie acid tert-butyl ester O.
Si M. W. 355.60 C19H37NO3Si Step A
In a manner similar to the methods described in Example 111a Step A. Step B., Step C., and Step D., 1,1-bis(hydroxymethyl)-cyclobutane (Waterstone) (3.8 g, 33 mmol) was reacted with thionyl chloride (8 g, 72 mmol) in anhydrous ethyl ether at 0 C, then reacted with NaCN (2 g, 41 mmol) in anhydrous dimethyl sulfoxide 120 C for 18 h, then treated with tert-butyldimethylehlorosilane (1 g, 6 mmol) and imidazole (1 g, 15 mmol) in dichloromethane at room temperature, follone by the reaction with DIBAL (1 M in heptane, 6.4 mL, 6.4 mmol) at 0 C to give [1-(tert-butyl-dimethyl-silanyloxym ethyl)-cyclobutyl]-acetaldehyde as a colorless oil (Yield: 0.48 g, 6% for four steps).
Step B
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.26 g, 2 mmol) was reacted with [1-(tert-butyl-dimethyl-silanyloxym ethyl)-cyclobutyl]-acetaldehyde (0.48 g, 2 nimot) in CH2C12 at room temperature for 18 h to give [2-[1-(tert-tutyl-dimethyl-silanyloxymethyl)-cyclopropyl]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.71 g, 100%).
Example 115b Preparation of intermediate rac-(2R,3S,4R,5S)-5-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutylmethy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester Cl F
=NH V
0 k_ Cl FN Si-M. W. 665.73 C34H44C12F2N203Si In a manner similar to the method described in Example 100b, [241-(tert-tutyl-dimethyl-silanyloxymethyl)-cyclopropyli-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 115a (0.71 g, 2 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (0.49 g, 1.6 mmol) prepared in Example 52a, AgF
(0.3 g, 2.4 mmol), and triethylamine (0.55 mL, 4 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (1 ml) in tert-butanol (15 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-5-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutylmethyl]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a yellow gum (0.7 g, 67%).
Example 115c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid cl F0/OH
NH
m CI F\\ N
FOH
M. W. 495.36 C24H22C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutylmethy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 115b (0.7 g, 1 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.6 g, 100%).
Example 115d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
*0H
NH.
CI FN OH
M. W. 582.48 C28H3IC12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 115c (0.6 g, 1 mmol) was reacted -with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.43 g, 3 mmol), HATU (0.67 g, 1.8 mmol) and iPr2NEt (0.86 mL, 4.9 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.32 g, 56%).
FIRMS (ES-) ITI/Z Catat for C28H31C12F2N304* H [(M+H )1: 582.1733; found:
582.1733.
Example 115e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
*OH
NH
1101 µ O
CI H
M. W. 582.48 C28H31C12F2N304 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.25 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (104 mg, 41%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (103 mg, 41%).
HR IS (ES ) Trih. Ca led for C28H31C12F2N3041- H [( M fil)]: 582.1733, found:
582.1733.
Example 116a Preparation of intermediate [5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid methyl ester I
M. W. 315.53 C16H33NO3Si Step A
To the solution of 3,3-dimethylglutaric acid (Aldrich) (5.1 g, 32 mmol) in anhydrous tetrahydrofuran (100 mL) at 0 C was added a solution of BH3.THF (1 M, 100 mL, 100 mmol).
The reaction mixture was stirred at room temperature for 18 h. Aqueous HC1 solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated.
The residue was purified by chromatography (Et0Ac) to give 3,3-dimethyl-pentane-1,5-diol as a colorless oil (1.5 g, 34%).
Step B
A mixture of 3,3-dimethyl-pentane-1,5-diol (1.5 g, 11 mmol) and imidazole (1.4 g, 20 mmol) in dichloromethane (50 mL) was added tert-butyldimethylchlorosilane (1.7 g, 1 1 mmol). The reactiom mixture was stirred at room temperature for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with dichloromethane. The combined organic layers wer washed with brine, dried over MgSO4, concentrated to give 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentan-1-ol as a colorless oil (2.7 g, 100%).
Step C
To a solution of oxalyl chloride (0.97 mL, 11 mmol) (Aldrich) in dichloromethane (20 mL) at -78 C was added the solution of dimethyl sulfoxide (1.6 mL, 22 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentan-1-ol (2.5 g, 10 mmol) in dichloromethane (10 mL) was added dropwise.
The reaction mixture was stirred at -78 C for 15 min. Triethylamine (5 mL, 36mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentanal as a light yellow oil (Yield: 1.75 g, 71%).
Step D
In a manner similar to the method described in Example la, glycine methyl ester hydrochloride (0.9 g, 7.2 mmo1) was reacted with 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentanal (1.75 g, 7.2 nitwit) and triethylamine (I .4() rn[.; 11 'mail) in CH2C12 at room temperature for 18 h to give [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid methyl ester as a colorless oil (2.3 g, 100%).
Example 116b Preparation of intermediate rac-(2R,3S,4R,5S)-5-[4-(tert-tutyl-dimethyl-silanyloxy)-2,2-dimethyl-buty1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid methyl ester CI F
NH
101""
CI F N 0-Si-M. W. 625.66 C31f140C12F2N203Si In a manner similar to the method described in Example lc, [5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pent-(E)-ylideneamincfl-acetic acid methyl ester prepared in Example 116a (6.4 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (1.58 g, 5.1 mmol) prepared in Example 52a, AgF (1g, 7.8 mmol), and triethylamine (1.8 mL, 13 mmol) in dichloromethane (100 mL) at room temperature for 48 h to give rac-(2R,3S,4R,5S)-544-(tert-tutyl-dimethyl-silanyloxy)-2,2-dimethyl-buty1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid methyl ester as a yellow gum (1.6 g, 50%).
Example 116c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid CI F oe0H
. 1; NH
OH
Cl FN
M. W. 483.35 C23H22C12F2N203 To rac-(2R,3S,4R,5S)-5-[4-(tert-tutyl-dimethyl-silanyloxy)-2,2-dimethyl-buty1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid methyl ester prepared in Example 116b (0.7 g, 1.1 mmol) in tetrahydrofuran (10 mL) was added tetrahydrofuran solution (1 M, Aldrich) of TBAF (1.34 mL, 1.3 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated, the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over Mg504, and concentrated. The residue was dissolved into tetrahydrofuran (10 mL), and an aqueous solution (1 M) of LiOH (10 mL, 10 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The "pH" of the mixture was adjusted to ¨4-5 by aqueous HC1 solution. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, concentrated to give intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid as a light yellow solid (0.3 g, 54%) Example 116d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide H
CI F
=NH OH
1101 F µµ OH
CI N
M. W. 584.49 C28H33C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid prepared in Example 116c (0.18 g, 0.36 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.16 g, 1 mmol), HATU (0.25 g, 0.65 mmol) and iPr2NEt (0.07 mL, 0.43 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 54%).
HRMS (ES ') 111/Z Calcd for C28H33C12F2N304-,- H [(1\4+H )-]: 584.1889, found:
584.1889.
Example 116e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI F
OH
NH
CI
M. W. 584.49 C28H3302F2N304 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide(0.35 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (157 mg, 45%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (155 mg, 44%).
FIRMS (ES') miz Calcd for C28H33C12F2N304 H [0,1-F I-I )' j: 584.1889, found:
584.1 891.
Example 117a Preparation of intermediate [2-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enyl]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester ik M. W. 381.64 C21F139NO3Si Step A
In a manner similar to the methods described in Example 111a Step A. Step B., Step C., and Step D., 3-cyclohexene-1,1-dimethanol (Aldrich) (5.3 g, 37 mmol) was reacted with thionyl chloride (15 g, 135 mmol) in anhydrous ethyl ether at 0 C, then reacted with NaCN (3 g, 61 mmol) in anhydrous dimethyl sulfoxide 120 C for 18 h, then treated with tert-butyldimethylchlorosilane (3.9 g, 26 mmol) and imidazole (2.4 g, 36 mmol) in dichloromethane at room temperature, follone by the reaction with DIBAL (1 M in heptane, 26 mL, 26 mmol) at 0 C to give 1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enecarbaldehyde as a light yellow oil (Yield: 6 g, 64% for four steps).
Step B
In a manner similar to the method described in Example la, glycine tert-butyl ester (1.2 g, 9 mmol) was reacted with 1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enecarbaldehyde (2.5 g, 9 mi-nol) in CH2C12 at room temperature for 18 h to give [241-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enyli-eth-(E)-ylideneaminoi-acetic acid tert-butyl ester as a light yellow oil (3.5 g, 100%).
Example 117b Preparation of intermediate rac-(2R,3S,4R,5S)-5-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enylmethy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
= NH 0, Cl FN Si-.
M. W. 691.77 C36H46C12F2N203Si In a manner similar to the method described in Example 100b, [241-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-eny1]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 117a (3.5 g, 9 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (2.3 g, 7 mmol) prepared in Example 52a, AgF (1.4 g, 11 mmol), and triethylamine (2.6 mL, 19 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (9 ml) in tert-butanol (10 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-5-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enylmethy1]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (2.6 g, 51%).
Example 117c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
= NH 0, LOH
F. 11 OH
CI FN
M. W. 521.40 C26H24C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-541-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enylmethyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 117b (2.6 g, 3.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.2 g, 92%).
Example 117d Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl]-amide CI F
41' NH O*
CI F OH
M. W. 648.58 C33H37C12F2N304 A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 117c (1 g, 1.6 mmol), HATU (1.07 g, 2.8 mmol) and iPr2NEt (1.37 mL, 7.8 mmol) in CH2C12 (10 mL) was stirred at room temperature for 18 h. The mixture was then diluted with CH2C12 and washed with water, brine. The organic layer was separated, the aqueous layer was extracted with CH2C12. The organic layers were combined, and concentrated.
The residue was dissolved into tetrahydrofuran (5 mL), and aqueous saturated K2CO3 (5 mL) was added. The mixture was stirred at room temperature for 30 min, then partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (Et0Ac) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide as a white solid (0.48 g, 47%) Example 117e Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
=OH
NH 0, Cl H
M. W. 608.51 C30H33C12F2N304 In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 117d (0.2 g, 0.3 mmol) was reacted with aqueous HC1 solution (1 N, lmL, 1 mol) in tetrahydrofuran (9 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.14 g, 75%).
HRNIS (ES) ntlz Calcd for C301133C12F2N304-4- H [(M+1-1) ]: 608.1889, found:
608.1888.
Example 118a Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide H
CI F
. NH at-Cl µµN OH
F
M. W. 650.60 C33H39C12F2N304 To a solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide (0.28 g, 0.43 mmol) prepared in Example 117d in ethyl acetate (10 mL) was added Pt02 (0.1 g). The suspension was shaken vigorously under H2 atmosphere (50 psi) for 1 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylFamide as a white solid (0.27 g, 96%) Example 118b Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide H
CI F
0., =
NH OH .
1101 µ µµN OH
CI F
M. W. 610.51 C30H35C12F2N304 In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 118a (0.27 g, 0.4 mmol) was reacted with aqueous HC1 solution (1 N, lmL, 1 mol) in tetrahydrofiiran (9 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.23 g, 91%).
FIRMS (ES ')I11/Z Calcd for C301-135C12F2N304-,- H [(M+H )]: 610.2046, found:
610.2042.
Example 119a Preparation of intermediate [5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester oo OC) i /
M. W. 401.67 C211-143NO4Si Step A
To the solution of 3,3-dimethyl-pentane-1,5-diol (1.5 g, 11 mmol) prepared in Example 116a Step A. in anhydrous dimethylformamide (15 mL) was added NaH (60%, 0.68 g, 17 mmol). The mixture was stirred at room temperature for 15 min, then (2-bromoethoxy)-tert-butyldimethylsilane (3.3 g, 14 mmol) was added. The mixture was stiired at room temperature for 1 h. Water was added. The mixture was extracted with ethyl acetate twice.
The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes=1:3) to give 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentan-1-ol as a yellow oil (0.3 g, 9%).
Step B
To a solution of oxalyl chloride (0.1 mL, 1 mmol) (Aldrich) in dichloromethane (5 mL) at -78 C
was added the solution of dimethyl sulfoxide (0.16 mL, 2.2 mmol) in dichloromethane (1 mL) dropwise. After 5 mins, the solution of 542-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentan-1-ol (0.3 g, 1 mmol) in dichloromethane (1 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (0.5 mL, 3.6 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 542-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentanal as a yellow oil (Yield: 0.27 g, 94%).
Step C
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.13 g, 1 mmol) was reacted vith 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentanal (0.27 g, I mntot) in CH2C12 at room temperature for 18 h to give [5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.4 g, 100%).
Example 119b Preparation of intermediate rac-(2R,3S,4R,5S)-5- {4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2,2-dimethyl-butyl} -3 -(3 -chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester Ci F
= NH
01µ"µ
Cl F N
Si /
M. W. 711.80 C36H50C12F2N204Si In a manner similar to the method described in Example 100b, [542-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 119a (0.4 g, 1 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (0.3 g, 1 mmol) prepared in Example 52a, AgF
(0.2 g, 1.5 mmol), and triethylamine (0.3 mL, 2.4 mmol) in dichloromethane (50 mL) at room temperature for 18 h, followed by the reaction with DBU (1 ml) in tert-butanol (2 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-5- {4- [2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2,2-dimethyl-butylf -3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white gum (0.49 g, 60%).
Example 119c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- {2,2-dimethy1-442-(2,2,2-trifluoro-acetoxy)-ethoxy]-butyl}-pyrrolidine-2-carboxylic acid trifluoroacetic acid NH=
F. 11 1,F 0 0-'1"))r-F
Cl FN 0 M. W. 483.35 C23H22C12F2N203.C2HF302 To a solution of rac-(2R,3S,4R,5S)-5-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2,2-dimethyl-butyl} -3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 119b (0.49 g, 0.55 mmol) in dichloromethane (3 mL) at room temperature was added trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5- {2,2-dimethy1-4- [2-(2,2,2-trifluoro-aceto xy)-ethoxy] -butyl} -pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow oil (0.37 g, 97%).
Example 119d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[4-(2-hydroxy-ethoxy)-2,2-dimethyl-butyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
OH
4* NH
IISI"01 ; \\NI
M. W. 628.54 C30H37C12F2N303 In a manner similar to the method described in Examples 117d and 117e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-{2,2-dimethyl-442-(2,2,2-trifluoro-acetoxy)-ethoxy]-buty1}-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 119c (0.37 g, 0.58 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.25 g, 1.7 mmol), HATU (0.4 g, 1 mmol) and iPr2NEt (0.5 mL, 2.9 mmol) in CH2C12 at room temperature for 20 h, then treated with aqueous saturated K2CO3 solution in tetrahydrofuran, followed by reaction with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[4-(2-hydroxy-ethoxy)-2,2-dimethyl-butyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a light yellow solid (90 mg, 25%).
FIRMS (ES )1111Z Calcd for C30H37C12F2N305 II RM -F-I-I)' j: 628.2151 found:
628.2150.
Example 120a Preparation of intermediate [5-azido-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester 0õ01 ,.N
'N
M. W. 268.36 C13H24N402 Step A
To the solution of 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentan-l-ol (1.1 g, 5 mmol) prepared in Example 116a Step B. and triethylamine (1.39 mL, 10 mmol) in dichloromethane (50 mL) at 0 C was added a dichlormethane solution (10 mL) of methanesulfonyl chloride (Aldrich) (0.46 mL, 6mmol). The reaction mixture was stirred at 0 C for 1 h.
Water was added.
Organic layer was separated, the aqueous layer was extracted with dichlormethane. The combined organic layers were washed with diluted aqueous HC1 solution, saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give methanesulfonic acid 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentyl ester as a yellow oil (1.48 g, 99%).
Step B
To the solution of methanesulfonic acid 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentyl ester (1.48 g, 4.96 mmol) in anhydrous dimethylformamide (10 mL) was added NaN3 (1.6 g, 25 mmol). The reaction mixture was heated at 60 C for 18 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSaito give (5-azido-3,3-dimethyl-pentyloxy)-tert-butyl-dimethyl-silane as a yellow oil (0.8 g, 67%).
Step C
To a solution of (5-azido-3,3-dimethyl-pentyloxy)-tert-butyl-dimethyl-silane (0.8 g, 3 mmol) in tetrahydrofuran (5 mL) was added tetrahydrofuran solution (1 M, Aldrich) of TBAF (4.9 mL, 4.9 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes=1:3) to give 5-azido-3,3-dimethyl-pentan-1-ol as a colorless oil (Og, 76%) Step D
To a solution of oxalyl chloride (0.24 mL, 2.7 mmol) (Aldrich) in dichloromethane (12 mL) at -78 C was added the solution of dimethyl sulfoxide (0.38 mL, 5.5 mmol) in dichloromethane (1 mL) dropwise. After 5 mins, the solution of 5-azido-3,3-dimethyl-pentan-l-ol (0.39 g, 2.5 mmol) in dichloromethane (1 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (1.2 mL, 9 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 5-azido-3,3-dimethyl-pentanal as a yellow oil (Yield: 0.38 g, 99%).
Step C
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.32 g, 2.45 mmol) was reacted with 5-azido-3,3-dimethyl-pentanal 038 g, 2.45 irtmoi) in CH2C12 at room temperature for 18 h to give [5-azido-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (0.65 g, 100%).
Example 120b Preparation of intermediate rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
= NH
CI N.
+
F N
M. W. 578.49 C281131C12F2N502 In a manner similar to the method described in Example 100b, [5-azido-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 120a (0.65 g, 2.45 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (0.76 g, 2.45 mmol) prepared in Example 52a, AgF (0.47 g, 3.7 mmol), and triethylamine (0.55 mL, 6 mmol) in dichloromethane (80 mL) at room temperature for 18 h, followed by the reaction with DBU (3 ml) in tert-butanol (3 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a yellow gum (0.5 g, 36%).
Example 120c Preparation of intermediate rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F of0H
N H F. 11 'N:N -Cl F
M. W. 522.39 C24H23C12F2N503.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 120b (0.5 g, 0.86 mmol) was reacted .with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (0.54 g, 96%).
Example 120d Preparation of intermediate rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide Cl F 0 /.1\1-......r-e 0 = NH
c, M. W. 649.57 C31-136C12F2N603 In a manner similar to the method described in Examples 42c, rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 120c (0.54 g, 0.85 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.37 g, 2.54 mmol), HATU (0.58 g, 1.5 mmol) and iPr2NEt (0.74 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylFamide as a light yellow solid (0.5 g, 91%).
Example 120e Preparation of rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F OH
OH
NH
Cl M. W. 609.50 C28H32C12F2N603 In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 120d (40 mg, 0.06 mmol) was reacted with aqueous HC1 solution (1 N, 3 mL, 3 mol) in tetrahydrofuran (7 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (29 mg, 79%).
H R. MS (ES' ) raiz Cated fi,r C28H32C12F2N603 H [(M I 1) ]: 009, 1954, round:
609.1954.
Example 121a Preparation of intermediate rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide 0%, = : NH
101v" NH2 Cl M. W. 623.58 C31-138C12F2N403 In a manner similar to the method described in Examples 118a, rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 120d (0.5 g, 0.77 mmol) was treated with Pt02 and H2 in ethyl acetate to give rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl]-amide as a black gum (0.47 g, 98%) Example 121b Preparation of rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
OH
= NH
W."NH2 CI
M. W. 583.50 C28H34C12F2N403 In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 121a (50 mg, 0.08 mmol) was reacted with aqueous HC1 solution (1 N, 3 mL, 3 mol) in tetrahydrofuran (7 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (29 mg, 62%).
H R. MS (ES' ) rii/z Ca for C281-134C12F2N403 H [( M I i)1: 583.2049, fund:
583.2047.
Example 122a Preparation of intermediate rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide CI F
NH
cl Nric ;N
M. W. 665.61 C33H40C12F2N404 To a solution of rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide (60 mg, 0.096 mmol) prepared in Example 121a and triethylamine (0.033 mL, 0.24 mmol) in tetrahydrofuran (3 mL) was added acetyl chloride (0.08 mL, 0.11 mmol). The reaction mixture was stirred at room temperature for 30 min, then water was added. The mixture was partitioned between ethyl acetate and water.
Organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (2% Me0H in Et0Ac) to give rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide as a off white gum (60 mg, 94%) Example 122b Preparation of rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
OH
= NH
\Sk CI
M. W. 625.54 C30H36C12F2N404 In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 122a (60 mg, 0.09 mmol) was reacted with aqueous HO
solution (1 N, 1 mL, 1 mol) in tetrahydrofuran (5 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (50 mg, 89%).
FIRMS (ES-) rniz Calcd for C30H36C12F2N404: fl [0,1-F I-I )' j: 625.2155, found: 625.2151.
Example 123 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-methanesulfonylamino-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide =NH OH
C?µ ,0 OP' N \
CI
M. W. 661.59 C29H36C12F2N405S
In a manner similar to the method described in Examples 122a and 122b, rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide (60 mg, 0.096 mmol) prepared in Example 121a was reacted with triethylamine and methanesulfonyl chloride (13 mg, 0.11 mmol) in dichloromethane, followed by the reaction with aqueous HC1 solution in tetrahydrofuran to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-methanesulfonylamino-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (57 mg, 90%) HRMS (ES `) rniz Calcd idr C29H36C12F2N405S-4- H [(M H)"1: 6611825. found:
661.1821.
Example 124 Preparation of rac-(2R,3S,4R,5S)-5-(4-benzoylamino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
*
: OH
101µ"µ
M. W. 687.61 C35H38C12F2N404 In a manner similar to the method described in Examples 122a and 122b, rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl]-amide (80 mg, 0.13 mmol) prepared in Example 121a was reacted with triethylamine and benzoyl chloride (22 mg, 0.16 mmol) in tetrahydrofuran, followed by the reaction with aqueous HC1 solution in tetrahydrofuran to give rac-(2R,3S,4R,5S)-5-(4-benzoylamino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a off white solid (57 mg, 90%) HRMS (ES') /111Z Calcd for C35H38C12F2N404-E 1-1 [(M+1-1) 1: 687.2311. found:
687.2308 Example 125a Preparation of intermediate [3-methy1-3-(5-methyl-furan-2-y1)-but-(E)-ylideneamino]-acetic acid tert-butyl ester r M. W. 279.38 C16H25NO3 Step A
To a solution of dimethyl malonate (6.5 g, 49 mmol), 2-acetyl-5-methylfuran (6.1 g, 49 mmol) and pyridine (16 g, 200 mmol) in anhydrous tetrahydrofuran (300 mL) at 0 C
was added a dichloromethane solution (1 M) of TiC14 (100 mL, 100 mmol) during a period of 1 h. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 18 h. Water was added to quench the reaction. The mixture was extracted with ethyl ether.
The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;10) to give 2-[1-(5-methyl-furan-2-y1)-ethylidene]-malonic acid dimethyl ester as a yellow oil (3.7 g, 32%).
Step B
To a suspension of CuI (7.61 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) at -50 C was added methylmagnesium chloride (3 M, 27 mL, 80 mmol) during a period of 15 min. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to -50 C, a tetrahydrofuran solution (50 mL) of 241-(5-methyl-furan-2-y1)-ethylidene]-malonic acid dimethyl ester (3.7 g, 15.5 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 3 h. Aqueous saturated NH4C1 solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1:20, 1:10) to give 2[1-methy1-1-(5-methyl-furan-2-y1)-ethyl]-malonic acid dimethyl ester as a colorless oil (2.5 g, 63%).
Step C
To a solution of 2-[1-methy1-1-(5-methyl-furan-2-y1)-ethyl]-malonic acid dimethyl ester (2.5 g, 9.8 mmol) in DMSO (30 mL) was added LiC1 (1 g, 23.7 mmol) and H20 (0.17 mL, 9.8 mmol).
The reaction mixture was heated at 170 C for 3 h, then poured into a ice-water, extracted with ethyl acetate. The organic layer were separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1:20, 1:20) to give 3-methyl-3-(5-methyl-furan-2-y1)-butyric acid methyl ester as a colorless oil (1.5 g, 78%).
Step D
To a solution of 3-methy1-3-(5-methyl-furan-2-y1)-butyric acid methyl ester (1.5 g, 7.8 mmol) in anhydrous tetrahydrofuran (50 mL) at 0 C was added a tetrhydrofuran solution (1 M) of LiAlF14 (10 mL, 10 mmol) under nitrogen. The reaction mixture was stirred at 0 C for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated to give 3-methy1-3-(5-methyl-furan-2-y1)-butan-1-ol as a yellow oil (1.2 g, 77%).
Step E
To a solution of oxalyl chloride (0.91 g, 7.1 mmol) (Aldrich) in dichloromethane (20 mL) at -78 C was added the solution of dimethyl sulfoxide (1 mL, 14.3 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 3-methy1-3-(5-methyl-furan-2-y1)-butan-l-ol (1.2 g, 7.1 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (3.6 mL, 26 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3-methy1-3-(5-methyl-furan-2-y1)-butyraldehyde as a yellow oil (Yield: 1 g, 83%).
Step F
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.79 g, 6 mmol) was reacted vviih 3-methyl-3-(5-methyl-furan-2-y1)-butyraldehyde (i g, o mmoi) in CH2C12 at room temperature for 5 h to give [3-methy1-3-(5-methyl-furan-2-y1)-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.7 g, 100%).
Example 125b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-y1)-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
= NH
I
M. W. 589.52 C31H32C12F2N203 In a manner similar to the method described in Example 100b, [[3-methy1-3-(5-methyl-furan-2-y1)-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 125a (1.7 g, 6 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (1.48 g, 4.8 mmol) prepared in Example 52a, AgF (0.9 g, 7 mmol), and triethylamine (1.7 mL, 12 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (5.7 ml) in tert-butanol (10 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-y1)-propy1]-pyrrolidine-2-carboxylic acid tert-butyl ester as a yellow solid (1.3 g, 46%).
Example 125c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Cl F
= NH
F. 11 FOH
M. W. 533.41 C27H24C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-542-methyl-2-(5-methyl-furan-2-y1)-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 125b (1.3 g, 2.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-y1)-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a brown solid (1.3 g, 92%).
Example 125d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-y1)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
OH
= NH
Cl FN /
M. W. 620.52 C311133C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-y1)-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 125c (0.6 g, 0.93 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.4 g, 2.8 mmol), HATU (0.6 g, 1.7 mmol) and iPr2NEt (0.8 mL, 4.6 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-y1)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.16 g, 29%).
HRMS (ES) `)milz Caled for C3 H33 Cl2F2N3 04+ H [(1\,4+1-1) ]: 620.1889, found: 620.1889.
Example 126a Preparation of intermediate [4-(4-methoxy-phenyl)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid methyl ester OTO.
M. W. 277.37 C16H23NO3 Step A.
Under Argon, a mixture of NaOH (2.8 g, 70 mmol),tetrabutylammonium iodide (0.6 g, 1.6 mmol) in benzene (8 mL) and H20 (2.8 mL) was heated at 70 C to form a homogeneous mixture. A mixture of 4-methoxybenzyl chloride (Aldrich) (10 g, 64 mmol) and isobutyraldehyde (5.76 g, 80 mmol) in benzene (22 mL) was added dropwise. The resulting reaction mixture was heated at 70 C for 3 h. The mixture was cooled, extracted with ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate.
The organic layers were combined, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;30) to give 2-(4-methoxy-phenyl)-2-methyl-propionaldehyde as a colorless oil (4.1 g, 33%).
Step B
To a mixture of methoxymethyl triphenylphosphonium chloride (14.6 g, 42 mmol) in anhydrous tetrahydrofuran (60 mL) at 0 C was a tetrahydrofuran solution (Aldrich, 1 M) of LiHMDS (42 mL, 42 mmol) dropwise. After the addition was finished, the reaction mixture was stirred at 0 C
for 20 min. Then a tetrahydrofuran solution (40 mL) of 2-(4-methoxy-pheny1)-2-methyl-propionaldehyde (4.1g, 21 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 1 h. Water was added to quench the reaction. The mixture was extracted with ethyl acetate twice. The organic layers were combined, concentrated.
The residue was purifed by chromatography (Et0Ac:hexanes=1:30, 1:20) to give a yellow oil (3.5 g). The oil was dissolved into a solution of aqueous HC1 solution (2 N, 50 mL, 100 mmol) and tetrahydrofuran (50 mL). The reaction mixture was heated at reflux for 1 h, then cooled to room temperature and concentrated. The residue partitioned between ethyl acetate and water.
The organic layer was separated, concentrated. The residue was purified by chromatography (Et0Ac:hexanes=1:10,1:5) to give 3-(4-methoxy-phenyl)-3-methyl-butyraldehyde as a colorless oil (2.1 g, 47%).
Similar transformations have been reported in US6531494 and the procedures described were used without modifications.
Step C
In a manner similar to the method described in Example la, glycine methyl ester hydrochloride (1.25 g, 10 mmol) was reacted with 3-(4-methoxy-phenyl)-3-methyl-butyraldehyde (2.1 g, 10 mniol) and triethyIarnine (2.2 g. 20 nlimo I) in CH2C12 at room temperature for 5 h to give [4-(4-methoxy-pheny1)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid methyl ester as a colorless oil (2.7 g, 97%).
Example 126b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[3-(4-methoxy-pheny1)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid methyl ester CI F
= NH
sor *
CI FN
M. W. 587.50 C31-130C12F2N203 In a manner similar to the method described in Example lc, [4-(4-methoxy-pheny1)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid methyl ester prepared in Example 126a (2.7 g, 9.7 mmol) was v.:acted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (3.1 g, 10 mmol) prepared in Example 52a, AgF (1.27 g, 10 mmol), and triethylamine (6 g, 60 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[3-(4-methoxy-pheny1)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid methyl ester as a yellow solid (4 g, 70%).
Example 126c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[3-(4-methoxy-pheny1)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid Ci F0/OH
= NH
0.
CI FN
M. W. 573.47 C30H28C12F2N203 To rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-543-(4-methoxy-pheny1)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid methyl ester prepared in Example 126b (4 g, 6.8 mmol) in tetrahydrofuran (60 mL) was added an aqueous solution (1 N) of NaOH (20 mL, 20 mmol) and methanol (20 mL). The reaction mixture was stirred at room temperature for 3 h. The "pH" of the mixture was adjusted to ¨4-5 by aqueous HC1 solution. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over Mg504, concentrated to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-pheny1)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid as a light yellow solid (4 g, 100%) Example 126d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[3-(4-methoxy-pheny1)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
OH
NH
CI
M. W. 660.59 C34H37C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[3-(4-methoxy-pheny1)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid prepared in Example 126c (0.5 g, 0.87 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.25 g, 1.7 mmol), HATU (0.6 g, 1.7 mmol) and iPr2NEt (0.45 mL, 2.6 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[3-(4-methoxy-pheny1)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.16 g, 29%).
FIRMS (ES') ITLIZ Cale' for C34H37C12F2N304--E 1-1 [(M+f-Ea 660.2202. found:
660.2198.
Example 127a Preparation of intermediate [3-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester I
M. W. 370.54 C23/{34N202 Step A
To a tetrahydrofuran solution (Aldrich, 1.8 M) of LDA (60 mL, 109 mmol) at -50 C was added isobutyric acid ethyl ester (Alfa) (12.2 mL, 91 mmol) dropwise. The reaction mixture was stirred -50 C for 1 h, then a tretrahydrofuran solution (10 mL) of 1-benzyl-piperidin-4-one (12 mL, 68 mmol) was added dropwise. The reaction mixture was warmed up to room temperature and stirred for 18 h. Aqueous saturated NH4C1was added to quench the reaction. The mixture was extracted with ethyl ether. The organic layer was separated, and the aqueous layer was extracted with ethyl ether. The organic layers were combined, washed with brine, water, dried over MgSO4, and concentrated to give 2-(1-benzy1-4-hydroxy-piperidin-4-y0-2-methyl-propionic acid ethyl ester as an orange oil (18.5 g, 89%).
Step B
To a solution of 2-(1-benzy1-4-hydroxy-piperidin-4-y1)-2-methyl-propionic acid ethyl ester (18.5 g, 61 mmol) in chloroform (75 mL) was added thionyl chloride (8.9 mL, 120 mmol) and dimethylformamide (0.17 mL). The reaction mixture was heated at 100 C for 18 h, then cooled to room temperature and concentrated. To the resulting residue was added aqueous NaOH
solution (10 N) to adjust the "pH" of the mixture to basic. The mixture was then extracted with ethyl ether twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give 2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propionic acid ethyl ester as a brown oil (13 g, 75%).
Step C
To a solution of 2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propionic acid ethyl ester (6 g, 21 mmol) in anhydrous tetrahydrofuran 75 mL) at 0 C was added a tetrhydrofuran solution (1 M) of LiA1H4 (84 mL, 84 mmol) under nitrogen. The reaction mixture was heated at reflux for 3 h, then cooled to room temperature. Water and aqueous NaOH solution (2N) was added. The mixture was filtered to remove the precipitate, and the filtrate was concentrated. Water was added, and the mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated to give 2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propan-1-ol as a brown oil (4.73 g, 77%).
Step D
To a solution of oxalyl chloride (2.46 mL, 28 mmol) (Aldrich) in dichloromethane (150 mL) at -78 C was added the solution of dimethyl sulfoxide (4 mL, 56 mmol) in dichloromethane (25 mL) dropwise. After 5 mins, the solution of 2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propan-1-ol (6.3 g, 25.6 mmol) in dichloromethane (25 mL) was added dropwise.
The reaction mixture was stirred at -78 C for 15 min. Triethylamine (12.8 mL, 92 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 241-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propionaldehyde as a brown oil (Yield: 5.6 g, 89%).
Step E
To a mixture of methoxymethyl triphenylphosphonium chloride (12.6 g, 37 mmol) in anhydrous tetrahydrofuran (50 mL) at 0 C was a tetrahydrofuran solution (Aldrich, 1 M) of LiHMDS (46 mL, 46 mmol) dropwise. After the addition was finished, the reaction mixture was stirred at 0 C
for 20 min. Then a tetrahydrofuran solution (40 mL) of 2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propionaldehyde (5.6 g, 23 mmol) was added. The reaction mixture was stirred at 0 C for 2 h. Water was added to quench the reaction. The mixture was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was dissolved into a solution of aqueous HC1 solution (2 N, 50 mL, 100 mmol) and tetrahydrofuran (50 mL). The reaction mixture was heated at reflux for 30 min, then cooled to room temperature and concentrated. The residue partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by chromatography (Et0Ac:hexanes=1:3) to give 3-0 -bonzy1-1,2,3,6-teftahydro-pyridin-4-0-3-1m.thyl-butyraidehyde as a yellow oil (1.65 g, 28%).
Step F
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.84 g, 6.4 mmol) was reacted with 3-( 1 -berizyi-1,2,3,6-tetrahydro-pyridin-4-y1 )-3-methyl-butyra ide1/2,rde (1.65 g, 6.4 Inmo I) in CH2C12 at room temperature for 5 h to give [3-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (2.4 g, 100%).
Example 127b Preparation of intermediate rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-343-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester CI
NH
CI F ¨ µ N =
M. W. 680.67 C381-141C12F2N303 In a manner similar to the method described in Example 100b, [3-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 127a (2.4 g, 6.4 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.8 g, 6.4 mmol) prepared in Example 52a, AgF (1.3 g, 10 mmol), and triethylamine (2 mL, 14.5 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (7 ml) in tert-butanol (30 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow solid (3.2 g, 81%).
Example 127e Preparation of intermediate rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid Ci F OH
= NH
F. 11 µ'%
CI FN N
M. W. 626.58 C34H35C12F2N303.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 127b (1.5 g, 2.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (1.6 g, 98%).
Example 127d Preparation of intermediate rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide CI F
= NH
CI FN N *
M. W. 751.75 C41H46C12F2N403 In a manner similar to the method described in Examples 42c, rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 127c (1.6 g, 2.2 mmol) was reacted with 24(S)-2,2-dimethy141,3]dioxolan-4-y1)-ethylamine (0.94 g, 6.5 mmol), HATU (2.5 g, 6.5 mmol) and iPr2NEt (2.3 mL, 13 mmol) in CH2C12 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide as a light yellow gum (1 g, 83%).
Example 127e Preparation of rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1 ,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
=OH
NH
Cl FN / N *
M. W. 711.68 C38H42C12F2N403 In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl]-amide prepared in Example 127d (1 g, 1.3 mmol) was reacted with aqueous HC1 solution (1 N, 5 mL, 5 mol) in tetrahydrofuran (5 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propyl]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 32%).
FIRMS (ES )1/1/z Caled for C38H42C12F2N403 II [0,114-1)' j: '711.2675, found:
71 1.2675, Example 128 Preparation of rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-piperidin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI F
,NH OH
CI \\N
N *
M. W. 713.69 C38I-144C12F2N403 In a manner similar to the method described in Examples 118a, rac-(2R,3S,4R,55)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide prepared in Example 127e (60 mg, 0.08 mmol) was treated with Pt02 and H2 in ethyl acetate to give rac-(2R,3S,4R,5S)-542-(1-benzyl-piperidin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a off white solid (15 mg, 25%) FIRMS (ES) miz Calf:A for C38H44C12F2N4034- 11 [(M11-1) j: 713.2832, (bund:
713.2837, Example 129a Preparation of intermediate [3-(3,6-dihydro-2H-pyran-4-y1)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester I
M. W. 281.40 C16H27NO3 Step A
To a hexane solution (Aldrich, 2 M) of LDA (78 mL, 160 mmol) in tetrahydrofuran (100 mL) at -50 C was added a solution of isobutyric acid ethyl ester (Alfa) (17 mL, 127 mmol) in tetrahydrofuran (20 mL) dropwise. The reaction mixture was stirred -50 C for 1 h, then a tretrahydrofuran solution (10 mL) of tetrahydro-pyran-4-one (Aldrich) (9.8 g, 98 mmol) was added dropwise. The reaction mixture was warmed up to room temperature and stirred for 18 h.
Aqueous saturated NH4C1was added to quench the reaction. The mixture was extracted with ethyl ether. The organic layer was separated, and the aqueous layer was extracted with ethyl ether. The organic layers were combined, washed with brine, water, dried over MgSO4, and concentrated to give 2-(4-hydroxy-tetrahydro-pyran-4-y1)-2-methyl-propionic acid ethyl ester as a yellow oil (19.5 g, 92%).
Step B
To a solution of 2-(4-hydroxy-tetrahydro-pyran-4-y1)-2-methyl-propionic acid ethyl ester (19.5 g, 90 mmol) in chloroform (100 mL) was added thionyl chloride (13.3 mL, 180 mmol) and dimethylformamide (0.28 mL). The reaction mixture was heated at 100 C for 18 h, then cooled to room temperature and concentrated. To the resulting residue was added aqueous NaOH
solution (10 N) to adjust the "pH" of the mixture to basic. The mixture was then extracted with ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give 2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propionic acid ethyl ester as a brown oil (17.6 g, 99%).
Step C
To a solution of 2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propionic acid ethyl ester (6 g, 30 mmol) in anhydrous tetrahydrofuran (75 mL) at 0 C was added a tetrhydrofuran solution (1 M) of LiA1H4 (100 mL, 100 mmol) under nitrogen. The reaction mixture was heated at reflux for 3 h, then cooled to room temperature. Water and aqueous NaOH solution (2N) was added. The mixture was filtered to remove the precipitate, and the filtrate was concentrated. Water was added, and the mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated to give 2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propan-1-ol as a brown oil (4.63 g, 98%).
Step D
To a solution of oxalyl chloride (2.84 mL, 33 mmol) (Aldrich) in dichloromethane (150 mL) at -78 C was added the solution of dimethyl sulfoxide (4.6 mL, 65 mmol) in dichloromethane (25 mL) dropwise. After 5 mins, the solution of 2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propan-1-ol (4.6 g, 29 mmol) in dichloromethane (25 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (14.8 mL, 110 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min.
Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propionaldehyde as a brown oil (Yield: 5.6 g, 89%).
Step E
To a mixture of methoxymethyl triphenylphosphonium chloride (31.3 g, 91 mmol) in anhydrous tetrahydrofuran (150 mL) at 0 C was a tetrahydrofuran solution (Aldrich, 1 M) of LiHMDS (110 mL, 110 mmol) dropwise. After the addition was finished, the reaction mixture was stirred at 0 C for 20 min. Then a tetrahydrofuran solution (40 mL) of 2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propionaldehyde (4.4 g, 28.5 mmol) was added. The reaction mixture was stirred at 0 C
for 1 h. Water was added to quench the reaction. The mixture was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was dissolved into a solution of aqueous HC1 solution (2 N, 50 mL, 100 mmol) and tetrahydrofuran (50 mL). The reaction mixture was heated at reflux for 30 min, then cooled to room temperature and concentrated. The residue partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by chromatography (Et0Ac:hexanes=1:3) to give 3-(3,6-dihy,iro-211-pyran-4-yi)-3-methy1-bulyra1dehytie as a brown oil (2.61 g, 54%).
Step F
In a manner similar to the method described in Example la, glycine tert-butyl ester (2 g, 15.5 mmol) was reacted wiLl/ 3-(3,6-dillydro-2ii-pyran-4-y1)-3-lneihyl-butyralciellyde (2.6 g. 15.5 minol) in CH2C12 at room temperature for 5 h to give [3-(3,6-dihydro-2H-pyran-4-y1)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (4.3 g, 100%).
Example 129b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propy1]-pyrrolidine-2-carboxylic acid tert-butyl ester CI Fle0-..K...
:H
M. W. 591.53 C31H34C12F2N203 In a manner similar to the method described in Example 100b, [3-(3,6-dihydro-2H-pyran-4-y1)-3-methyl-but-(E)-ylideneamincfl-acetic acid tert-butyl ester prepared in Example 129a (4.3 g, 15.5 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (3.8 g, 12.4 mmol) prepared in Example 52a, AgF (2.4 g, 19 mmol), and triethylamine (4.3 mL, 31mmo1) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (19 ml) in tert-butanol (18 mL) at 100 C
for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propy1]-pyrrolidine-2-carboxylic acid tert-butyl ester as a yellow gum(5.5 g, 75%).
Example 129c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
= NH
F
M. W. 535.42 C27H26C12F2N303.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-542-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 129b (5.5 g, 9.29 mmol) was rcacted v./id/ trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a dark solid (6 g, 99%).
Example 129d Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propy1]-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide Cl F
= NH
CI F µµN I 0 M. W. 662.61 C34H39C12F2N304 In a manner similar to the method described in Examples 42c, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-542-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 129c (0.8 g, 1.2 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.84 g, 2.2 mmol) and iPr2NEt (0.64 mL, 3.7 mmol) in CH2C12 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [24(S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl]-amide as a off white gum (0.6 g, 74%).
Example 129e Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propy1]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
OH
NH
CI F \\N I 0 M. W. 622.54 C31H35C12F2N304 In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-542-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propy1]-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl]-amide prepared in Example 129d (0.6 g, 0.9 mmol) was reacted with aqueous HC1 solution (1 N, 3 mL, 3 mol) in tetrahydrofuran (7 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.52 g, 93%).
FIRMS (ES) mlz Caled for C31H35C12F2N3O4 1 [(M j: 622.2046, found:
622.2046.
Example 130 Preparation of rac-(2R,3S,4R,5S)-3-(3-hloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(tetrahydro-pyran-4-y1)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI F
NH OH
M. W. 624.55 C311-13702F2N304 In a manner similar to the method described in Examples 118a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-542-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propy1]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide prepared in Example 127e (0.28 g, 0.45 mmol) was treated with Pt02 and H2 in ethyl acetate to give rac-(2R,3S,4R,5S)-3-(3-hloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(tetrahydro-pyran-4-y1)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a off white solid (0.15 g, 54%) FIRP,AS (ES `) Cal ed for C311-13702F2N304: j: 624.2202, found: 624.2207.
Example 131a Preparation of intermediate 2-((S)-2,2,5,5-ttramethyl-[1,3]dioxolan-4-y1)-ethylamine H2N,/"---X0 0¨ft M. W. 173.26 C9H19NO2 Step A.
To a suspension of L-(-)-malic aicd (Aldrich) (10.3 g, 77 mmol) in 2,2-dimethoxypropane (20 mL) was added p-toluenesulfonic acid monohydrate (0.4 g). The reaction mixture was stirred at room temperature for 30 min. The mixture was partitioned between water and dichloromethane.
The organic layer was separated, the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated to give ((S)-2,2-dimethy1-5-oxo-[1,3]dioxolan-4-y1)-acetic acid as a white solid (10.1 g, 75%).
Step B
To the solution of ((S)-2,2-dimethy1-5-oxo-[1,3]dioxolan-4-y1)-acetic acid (10.1 g, 58 mmol) in anhydrous tetrahydrofuran (20 mL) at 0 C was added a solution of BH3.THF (1 M, 70 mL, 70 mmol). The reaction mixture was stirred at room temperature for 2 h. Aqueous HC1 solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated.
The residue was purified by chromatography (Et0Ac) to give (S)-5-(2-hydroxy-ethyl)-2,2-dimethyl-[1,3]dioxolan-4-one as a colorless oil (6.8 g, 72%).
Step C
A mixture of (S)-5-(2-hydroxy-ethyl)-2,2-dimethyl-[1,3]dioxolan-4-one (6.8 g, 42 mmol) and imidazole (7.5 g, 107 mmol) in dimethylformamide (40 mL) was added tert-butyldimethylchlorosilane (7 g, 45 mmol). The reactiom mixture was stirred at room temperature for 18 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl acetate twice. The combined organic layers wer washed with brine, dried over MgSO4, concentrated to give (S)-542-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2,2-dimethyl-[1,3]dioxolan-4-one as a colorless oil (8.6 g, 74%).
Step D
To a solution of (S)-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethy1]-2,2-dimethyl-[1,3]dioxolan-4-one (8.5 g, 31 mmol) in diethyl ether (200 mL) at 0 C was added a diethyl ether (1.6 M) solution of methyllithium (50 mL, 78 mmol) dropwise. The reaction mixture was stirred at 0 C for 30 min. The mixture was poured into aqueous saturated NH4C1 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to give (S)-5-(tert-butyl-dimethyl-silanyloxy)-2-methyl-pentane-2,3-diol as a yellow oil (Yield: 6.8 g, 88%).
Step E
To a suspension of (S)-5-(tert-butyl-dimethyl-silanyloxy)-2-methyl-pentane-2,3-dio1 (6.8 g, 27 mmol) in 2,2-dimethoxypropane (35 mL) was added p-toluenesulfonic acid monohydrate (0.2g).
The reaction mixture was stirred at room temperature for 30 min. The mixture was partitioned between water and dichloromethane. The organic layer was separated, the aqueous layer was DEMANDES OU BREVETS VOLUMINEUX
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-Cl FN
M. W. 537.44 C27H28C12F2N203 In a manner similar to the method described in Example 100b[2-(3-methyl-oxetan-3-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 112a (1.6 g, 7 mmol) was reacted µ;vitl/ (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (1.7 g, 5.6 mmol) prepared in Example 52a, AgF (1.1 g, 8.5 mmol), and triethylamine (1.9 mL, 14 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (6.7 ml) in tert-butanol (20 mL) at 100 C for 2 h to rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow gum (1.0 g, 33%).
Example 112c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Cl F 0.e0H
= NH 0 u OP
Cl FN
M. W. 481.33 C23H20C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 112b (1.0 g, 1.9 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 91%).
Example 112d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI F
NH OH
1101P' \`%
CI FN
M. W. 568.45 C27H29C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 112c (0.5 g, 0.84 mmol) was reacted ,Nith 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU
(0.57 g, 1.5 mmol) and iPr2NEt (0.73 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.23 g, 48%).
HRMS (ES-) miz Calcd for C27H29C12F2N304,-- H[( V1+H)]: 568.1576, found:
568.1579.
Example 113a Preparation of intermediate [2-(3-ethyl-oxetan-3-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester I
M. W. 241.33 C13H23NO3 Step A
In a manner similar to the methods described in Example 112a Step A. Step B., and Step C., 3-ethyl-3-oxetanemethanol (TCI-US) (3.5 g, 30 mmol) was reacted with triethylamine (6.6 g, 60 mmol) and treated with NaCN (2.2 g, 46mmo1) in anhydrous dimethyl sulfoxide at 130 C, followed by the reaction with DIBAL (1 M in heptane, 27 mL, 27 mmol) in dichloromethane at 0 C to give (3-ethyl-oxetan-3-y1)-acetaldehyde as a light yellow oil (Yield: 2.5 g, 26% for three steps).
Step B
In a manner similar to the method described in Example la, glycine tert-butyl ester (1 g, 7.8 mmol) was reacted with (3-ethyl-oxetan-3-y1)-acetaldehyde (1 g, 7.8 mmol) in CH2C12 at room temperature for 18 h to give [2-(3-ethyl-oxetan-3-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (1.9 g, 100%).
Example 113b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester Cl F
= NH 0 CI F N
M. W. 551.41 C28H30C12F2N203 In a manner similar to the method described in Example 100b, [2-(3-ethyl-oxetan-3-y1)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 113a (1.9 g, 7.8 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.9 g, 6.2 mmol) prepared in Example 52a, AgF (1.2 g, 9.5 mmol), and triethylamine (2.2 mL, 16 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (7.5 ml) in tert-butanol (10 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (2 g, 58%).
Example 113c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
= NH 0 F.LOH
[10 CI FN
M. W. 495.36 C24H22C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 113b (2 g, 3.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2 g, 91%).
Example 113d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
NH OH
OP
CI
M. W. 582.47 C28I-131C12F2N304 In a manner similar to the method described in Examples 42c and 42d rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 105c (1 g, 1.6 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.7 g, 5 mmol), HATU (1.1 g, 3 mmol) and iPr2NEt (1.4 mL, 8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.56 g, 58%).
FIRMS (ES-) rwrz Ca'cc' for C28H31C12F2N304* H [(M+H )]: 582.1733, found:
582.1732.
Example 114a Preparation of intermediate [2-[1-(tert-tutyl-dimethyl-silanyloxymethyl)-cyclopropyl] -eth-(E)-ylideneamino]-acetic acid tert-butyl ester 00y-0 i )4-.
M. W. 341.57 C18H35NO3Si Step A
In a manner similar to the methods described in Example 111a Step A. Step B., Step C., and Step D., 1,1-bis(hydroxymethyl)-cyclopropane (Aldrich) (4 g, 39 mmol) was reacted with thionyl chloride (14 g, 126 mmol) in anhydrous ethyl ether at 0 C, then reacted with NaCN (2.4 g, 49 mmol) in anhydrous dimethyl sulfoxide 120 C for 18 h, then treated with tert-butyldimethylchlorosilane (1.4 g, 9 mmol) and imidazole (0.85 g, 13 mmol) in dichloromethane at room temperature, follone by the reaction with DIBAL (1 M in heptane, 8.3 mL, 8.3 mmol) at 0 C to give [1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopropyl]-acetaldehyde as a colorless oil (Yield: 1.3 g, 15% for four steps).
Step B
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.75 g, 5.7 mmol) was reacted with [1-(tert-butyl-dimethyl-silanyloxym ethyl)-cyclopropyl]-acetaldehyde ( .3 g, 5.7 rimiol) in CH2C12 at room temperature for 18 h to give [2-[1-(tert-tutyl-dimethyl-silanyloxymethyl)-cyclopropyl]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.9 g, 100%).
Example 114b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
= NH
A
OH
Cl FN
M. W. 537.44 C27H28C12F2N203 In a manner similar to the method described in Example 100b, [241-(tert-tutyl-dimethyl-silanyloxymethyl)-cyclopropyl]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 114a (1.9 g, 5.7 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.4 g, 4.6 mmol) prepared in Example 52a, AgF (0.89 g, 7.1 mmol), and triethylamine (1.6 mL, 12 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (5 ml) in tert-butanol (20 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (0.4 g, 30%).
Example 114c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Cl F 0.e0H
= NH
A u OH
Cl FN
M. W. 481.33 C23H20C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 114b (0.4 g, 0.74 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.4 g, 91%).
Example 114d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI F
= NHOH
A
1101 µ
CI FN OH
M. W. 568.45 C27H29C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyp-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 114c (0.4 g, 0.67 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.29 g, 2 mmol), HATU (0.46 g, 1.2 mmol) and iPr2NEt (0.58 mL, 3.4 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.15 g, 40%).
I-IRMS (S) Ca lcd ibr C27H29C12F2N304 4-i1 [(N/P j: 568.1576, fburid: 568.1578.
Example 114e Preparation of (2R,3S,4R,55)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
.NH OH
A
1101 µ
CI FN OH
M. W. 568.45 C27H29C12F2N304 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.12 g) was separated by chiral SFC chromatography to provide chiral (2R,35,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (46 mg, 38%) and chiral (2S,3R,4S,5R)-3-(3-ehloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (48 mg, 40%).
FIRMS (IS) raiz C.'alcd for C27H29C12F2N304 II [0,1 j: 568.1576, fi.)u:
568.1578, Example 115a Preparation of intermediate [2-[1-(tert-tutyl-dimethyl-silanyloxymethyl)-cyclobutyl]-eth-(E)-ylideneamino]-acetie acid tert-butyl ester O.
Si M. W. 355.60 C19H37NO3Si Step A
In a manner similar to the methods described in Example 111a Step A. Step B., Step C., and Step D., 1,1-bis(hydroxymethyl)-cyclobutane (Waterstone) (3.8 g, 33 mmol) was reacted with thionyl chloride (8 g, 72 mmol) in anhydrous ethyl ether at 0 C, then reacted with NaCN (2 g, 41 mmol) in anhydrous dimethyl sulfoxide 120 C for 18 h, then treated with tert-butyldimethylehlorosilane (1 g, 6 mmol) and imidazole (1 g, 15 mmol) in dichloromethane at room temperature, follone by the reaction with DIBAL (1 M in heptane, 6.4 mL, 6.4 mmol) at 0 C to give [1-(tert-butyl-dimethyl-silanyloxym ethyl)-cyclobutyl]-acetaldehyde as a colorless oil (Yield: 0.48 g, 6% for four steps).
Step B
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.26 g, 2 mmol) was reacted with [1-(tert-butyl-dimethyl-silanyloxym ethyl)-cyclobutyl]-acetaldehyde (0.48 g, 2 nimot) in CH2C12 at room temperature for 18 h to give [2-[1-(tert-tutyl-dimethyl-silanyloxymethyl)-cyclopropyl]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.71 g, 100%).
Example 115b Preparation of intermediate rac-(2R,3S,4R,5S)-5-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutylmethy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester Cl F
=NH V
0 k_ Cl FN Si-M. W. 665.73 C34H44C12F2N203Si In a manner similar to the method described in Example 100b, [241-(tert-tutyl-dimethyl-silanyloxymethyl)-cyclopropyli-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 115a (0.71 g, 2 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (0.49 g, 1.6 mmol) prepared in Example 52a, AgF
(0.3 g, 2.4 mmol), and triethylamine (0.55 mL, 4 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (1 ml) in tert-butanol (15 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-5-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutylmethyl]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a yellow gum (0.7 g, 67%).
Example 115c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid cl F0/OH
NH
m CI F\\ N
FOH
M. W. 495.36 C24H22C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutylmethy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 115b (0.7 g, 1 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.6 g, 100%).
Example 115d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
*0H
NH.
CI FN OH
M. W. 582.48 C28H3IC12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 115c (0.6 g, 1 mmol) was reacted -with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.43 g, 3 mmol), HATU (0.67 g, 1.8 mmol) and iPr2NEt (0.86 mL, 4.9 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.32 g, 56%).
FIRMS (ES-) ITI/Z Catat for C28H31C12F2N304* H [(M+H )1: 582.1733; found:
582.1733.
Example 115e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
*OH
NH
1101 µ O
CI H
M. W. 582.48 C28H31C12F2N304 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide (0.25 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (104 mg, 41%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (103 mg, 41%).
HR IS (ES ) Trih. Ca led for C28H31C12F2N3041- H [( M fil)]: 582.1733, found:
582.1733.
Example 116a Preparation of intermediate [5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid methyl ester I
M. W. 315.53 C16H33NO3Si Step A
To the solution of 3,3-dimethylglutaric acid (Aldrich) (5.1 g, 32 mmol) in anhydrous tetrahydrofuran (100 mL) at 0 C was added a solution of BH3.THF (1 M, 100 mL, 100 mmol).
The reaction mixture was stirred at room temperature for 18 h. Aqueous HC1 solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated.
The residue was purified by chromatography (Et0Ac) to give 3,3-dimethyl-pentane-1,5-diol as a colorless oil (1.5 g, 34%).
Step B
A mixture of 3,3-dimethyl-pentane-1,5-diol (1.5 g, 11 mmol) and imidazole (1.4 g, 20 mmol) in dichloromethane (50 mL) was added tert-butyldimethylchlorosilane (1.7 g, 1 1 mmol). The reactiom mixture was stirred at room temperature for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with dichloromethane. The combined organic layers wer washed with brine, dried over MgSO4, concentrated to give 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentan-1-ol as a colorless oil (2.7 g, 100%).
Step C
To a solution of oxalyl chloride (0.97 mL, 11 mmol) (Aldrich) in dichloromethane (20 mL) at -78 C was added the solution of dimethyl sulfoxide (1.6 mL, 22 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentan-1-ol (2.5 g, 10 mmol) in dichloromethane (10 mL) was added dropwise.
The reaction mixture was stirred at -78 C for 15 min. Triethylamine (5 mL, 36mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentanal as a light yellow oil (Yield: 1.75 g, 71%).
Step D
In a manner similar to the method described in Example la, glycine methyl ester hydrochloride (0.9 g, 7.2 mmo1) was reacted with 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentanal (1.75 g, 7.2 nitwit) and triethylamine (I .4() rn[.; 11 'mail) in CH2C12 at room temperature for 18 h to give [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid methyl ester as a colorless oil (2.3 g, 100%).
Example 116b Preparation of intermediate rac-(2R,3S,4R,5S)-5-[4-(tert-tutyl-dimethyl-silanyloxy)-2,2-dimethyl-buty1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid methyl ester CI F
NH
101""
CI F N 0-Si-M. W. 625.66 C31f140C12F2N203Si In a manner similar to the method described in Example lc, [5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pent-(E)-ylideneamincfl-acetic acid methyl ester prepared in Example 116a (6.4 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (1.58 g, 5.1 mmol) prepared in Example 52a, AgF (1g, 7.8 mmol), and triethylamine (1.8 mL, 13 mmol) in dichloromethane (100 mL) at room temperature for 48 h to give rac-(2R,3S,4R,5S)-544-(tert-tutyl-dimethyl-silanyloxy)-2,2-dimethyl-buty1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid methyl ester as a yellow gum (1.6 g, 50%).
Example 116c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid CI F oe0H
. 1; NH
OH
Cl FN
M. W. 483.35 C23H22C12F2N203 To rac-(2R,3S,4R,5S)-5-[4-(tert-tutyl-dimethyl-silanyloxy)-2,2-dimethyl-buty1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid methyl ester prepared in Example 116b (0.7 g, 1.1 mmol) in tetrahydrofuran (10 mL) was added tetrahydrofuran solution (1 M, Aldrich) of TBAF (1.34 mL, 1.3 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated, the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over Mg504, and concentrated. The residue was dissolved into tetrahydrofuran (10 mL), and an aqueous solution (1 M) of LiOH (10 mL, 10 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The "pH" of the mixture was adjusted to ¨4-5 by aqueous HC1 solution. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, concentrated to give intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid as a light yellow solid (0.3 g, 54%) Example 116d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide H
CI F
=NH OH
1101 F µµ OH
CI N
M. W. 584.49 C28H33C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid prepared in Example 116c (0.18 g, 0.36 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.16 g, 1 mmol), HATU (0.25 g, 0.65 mmol) and iPr2NEt (0.07 mL, 0.43 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 54%).
HRMS (ES ') 111/Z Calcd for C28H33C12F2N304-,- H [(1\4+H )-]: 584.1889, found:
584.1889.
Example 116e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI F
OH
NH
CI
M. W. 584.49 C28H3302F2N304 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide(0.35 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (157 mg, 45%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-hydroxy-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (155 mg, 44%).
FIRMS (ES') miz Calcd for C28H33C12F2N304 H [0,1-F I-I )' j: 584.1889, found:
584.1 891.
Example 117a Preparation of intermediate [2-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enyl]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester ik M. W. 381.64 C21F139NO3Si Step A
In a manner similar to the methods described in Example 111a Step A. Step B., Step C., and Step D., 3-cyclohexene-1,1-dimethanol (Aldrich) (5.3 g, 37 mmol) was reacted with thionyl chloride (15 g, 135 mmol) in anhydrous ethyl ether at 0 C, then reacted with NaCN (3 g, 61 mmol) in anhydrous dimethyl sulfoxide 120 C for 18 h, then treated with tert-butyldimethylchlorosilane (3.9 g, 26 mmol) and imidazole (2.4 g, 36 mmol) in dichloromethane at room temperature, follone by the reaction with DIBAL (1 M in heptane, 26 mL, 26 mmol) at 0 C to give 1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enecarbaldehyde as a light yellow oil (Yield: 6 g, 64% for four steps).
Step B
In a manner similar to the method described in Example la, glycine tert-butyl ester (1.2 g, 9 mmol) was reacted with 1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enecarbaldehyde (2.5 g, 9 mi-nol) in CH2C12 at room temperature for 18 h to give [241-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enyli-eth-(E)-ylideneaminoi-acetic acid tert-butyl ester as a light yellow oil (3.5 g, 100%).
Example 117b Preparation of intermediate rac-(2R,3S,4R,5S)-5-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enylmethy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
= NH 0, Cl FN Si-.
M. W. 691.77 C36H46C12F2N203Si In a manner similar to the method described in Example 100b, [241-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-eny1]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 117a (3.5 g, 9 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (2.3 g, 7 mmol) prepared in Example 52a, AgF (1.4 g, 11 mmol), and triethylamine (2.6 mL, 19 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (9 ml) in tert-butanol (10 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-5-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enylmethy1]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (2.6 g, 51%).
Example 117c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
= NH 0, LOH
F. 11 OH
CI FN
M. W. 521.40 C26H24C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-541-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enylmethyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 117b (2.6 g, 3.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.2 g, 92%).
Example 117d Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl]-amide CI F
41' NH O*
CI F OH
M. W. 648.58 C33H37C12F2N304 A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 117c (1 g, 1.6 mmol), HATU (1.07 g, 2.8 mmol) and iPr2NEt (1.37 mL, 7.8 mmol) in CH2C12 (10 mL) was stirred at room temperature for 18 h. The mixture was then diluted with CH2C12 and washed with water, brine. The organic layer was separated, the aqueous layer was extracted with CH2C12. The organic layers were combined, and concentrated.
The residue was dissolved into tetrahydrofuran (5 mL), and aqueous saturated K2CO3 (5 mL) was added. The mixture was stirred at room temperature for 30 min, then partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (Et0Ac) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide as a white solid (0.48 g, 47%) Example 117e Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
=OH
NH 0, Cl H
M. W. 608.51 C30H33C12F2N304 In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 117d (0.2 g, 0.3 mmol) was reacted with aqueous HC1 solution (1 N, lmL, 1 mol) in tetrahydrofuran (9 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.14 g, 75%).
HRNIS (ES) ntlz Calcd for C301133C12F2N304-4- H [(M+1-1) ]: 608.1889, found:
608.1888.
Example 118a Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide H
CI F
. NH at-Cl µµN OH
F
M. W. 650.60 C33H39C12F2N304 To a solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide (0.28 g, 0.43 mmol) prepared in Example 117d in ethyl acetate (10 mL) was added Pt02 (0.1 g). The suspension was shaken vigorously under H2 atmosphere (50 psi) for 1 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylFamide as a white solid (0.27 g, 96%) Example 118b Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide H
CI F
0., =
NH OH .
1101 µ µµN OH
CI F
M. W. 610.51 C30H35C12F2N304 In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 118a (0.27 g, 0.4 mmol) was reacted with aqueous HC1 solution (1 N, lmL, 1 mol) in tetrahydrofiiran (9 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(1-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.23 g, 91%).
FIRMS (ES ')I11/Z Calcd for C301-135C12F2N304-,- H [(M+H )]: 610.2046, found:
610.2042.
Example 119a Preparation of intermediate [5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester oo OC) i /
M. W. 401.67 C211-143NO4Si Step A
To the solution of 3,3-dimethyl-pentane-1,5-diol (1.5 g, 11 mmol) prepared in Example 116a Step A. in anhydrous dimethylformamide (15 mL) was added NaH (60%, 0.68 g, 17 mmol). The mixture was stirred at room temperature for 15 min, then (2-bromoethoxy)-tert-butyldimethylsilane (3.3 g, 14 mmol) was added. The mixture was stiired at room temperature for 1 h. Water was added. The mixture was extracted with ethyl acetate twice.
The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes=1:3) to give 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentan-1-ol as a yellow oil (0.3 g, 9%).
Step B
To a solution of oxalyl chloride (0.1 mL, 1 mmol) (Aldrich) in dichloromethane (5 mL) at -78 C
was added the solution of dimethyl sulfoxide (0.16 mL, 2.2 mmol) in dichloromethane (1 mL) dropwise. After 5 mins, the solution of 542-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentan-1-ol (0.3 g, 1 mmol) in dichloromethane (1 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (0.5 mL, 3.6 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 542-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentanal as a yellow oil (Yield: 0.27 g, 94%).
Step C
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.13 g, 1 mmol) was reacted vith 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentanal (0.27 g, I mntot) in CH2C12 at room temperature for 18 h to give [5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.4 g, 100%).
Example 119b Preparation of intermediate rac-(2R,3S,4R,5S)-5- {4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2,2-dimethyl-butyl} -3 -(3 -chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester Ci F
= NH
01µ"µ
Cl F N
Si /
M. W. 711.80 C36H50C12F2N204Si In a manner similar to the method described in Example 100b, [542-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 119a (0.4 g, 1 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (0.3 g, 1 mmol) prepared in Example 52a, AgF
(0.2 g, 1.5 mmol), and triethylamine (0.3 mL, 2.4 mmol) in dichloromethane (50 mL) at room temperature for 18 h, followed by the reaction with DBU (1 ml) in tert-butanol (2 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-5- {4- [2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2,2-dimethyl-butylf -3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white gum (0.49 g, 60%).
Example 119c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- {2,2-dimethy1-442-(2,2,2-trifluoro-acetoxy)-ethoxy]-butyl}-pyrrolidine-2-carboxylic acid trifluoroacetic acid NH=
F. 11 1,F 0 0-'1"))r-F
Cl FN 0 M. W. 483.35 C23H22C12F2N203.C2HF302 To a solution of rac-(2R,3S,4R,5S)-5-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2,2-dimethyl-butyl} -3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 119b (0.49 g, 0.55 mmol) in dichloromethane (3 mL) at room temperature was added trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5- {2,2-dimethy1-4- [2-(2,2,2-trifluoro-aceto xy)-ethoxy] -butyl} -pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow oil (0.37 g, 97%).
Example 119d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[4-(2-hydroxy-ethoxy)-2,2-dimethyl-butyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
OH
4* NH
IISI"01 ; \\NI
M. W. 628.54 C30H37C12F2N303 In a manner similar to the method described in Examples 117d and 117e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-{2,2-dimethyl-442-(2,2,2-trifluoro-acetoxy)-ethoxy]-buty1}-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 119c (0.37 g, 0.58 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.25 g, 1.7 mmol), HATU (0.4 g, 1 mmol) and iPr2NEt (0.5 mL, 2.9 mmol) in CH2C12 at room temperature for 20 h, then treated with aqueous saturated K2CO3 solution in tetrahydrofuran, followed by reaction with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[4-(2-hydroxy-ethoxy)-2,2-dimethyl-butyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a light yellow solid (90 mg, 25%).
FIRMS (ES )1111Z Calcd for C30H37C12F2N305 II RM -F-I-I)' j: 628.2151 found:
628.2150.
Example 120a Preparation of intermediate [5-azido-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester 0õ01 ,.N
'N
M. W. 268.36 C13H24N402 Step A
To the solution of 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentan-l-ol (1.1 g, 5 mmol) prepared in Example 116a Step B. and triethylamine (1.39 mL, 10 mmol) in dichloromethane (50 mL) at 0 C was added a dichlormethane solution (10 mL) of methanesulfonyl chloride (Aldrich) (0.46 mL, 6mmol). The reaction mixture was stirred at 0 C for 1 h.
Water was added.
Organic layer was separated, the aqueous layer was extracted with dichlormethane. The combined organic layers were washed with diluted aqueous HC1 solution, saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give methanesulfonic acid 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentyl ester as a yellow oil (1.48 g, 99%).
Step B
To the solution of methanesulfonic acid 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentyl ester (1.48 g, 4.96 mmol) in anhydrous dimethylformamide (10 mL) was added NaN3 (1.6 g, 25 mmol). The reaction mixture was heated at 60 C for 18 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSaito give (5-azido-3,3-dimethyl-pentyloxy)-tert-butyl-dimethyl-silane as a yellow oil (0.8 g, 67%).
Step C
To a solution of (5-azido-3,3-dimethyl-pentyloxy)-tert-butyl-dimethyl-silane (0.8 g, 3 mmol) in tetrahydrofuran (5 mL) was added tetrahydrofuran solution (1 M, Aldrich) of TBAF (4.9 mL, 4.9 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (Et0Ac:hexanes=1:3) to give 5-azido-3,3-dimethyl-pentan-1-ol as a colorless oil (Og, 76%) Step D
To a solution of oxalyl chloride (0.24 mL, 2.7 mmol) (Aldrich) in dichloromethane (12 mL) at -78 C was added the solution of dimethyl sulfoxide (0.38 mL, 5.5 mmol) in dichloromethane (1 mL) dropwise. After 5 mins, the solution of 5-azido-3,3-dimethyl-pentan-l-ol (0.39 g, 2.5 mmol) in dichloromethane (1 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (1.2 mL, 9 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 5-azido-3,3-dimethyl-pentanal as a yellow oil (Yield: 0.38 g, 99%).
Step C
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.32 g, 2.45 mmol) was reacted with 5-azido-3,3-dimethyl-pentanal 038 g, 2.45 irtmoi) in CH2C12 at room temperature for 18 h to give [5-azido-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (0.65 g, 100%).
Example 120b Preparation of intermediate rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
= NH
CI N.
+
F N
M. W. 578.49 C281131C12F2N502 In a manner similar to the method described in Example 100b, [5-azido-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 120a (0.65 g, 2.45 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (0.76 g, 2.45 mmol) prepared in Example 52a, AgF (0.47 g, 3.7 mmol), and triethylamine (0.55 mL, 6 mmol) in dichloromethane (80 mL) at room temperature for 18 h, followed by the reaction with DBU (3 ml) in tert-butanol (3 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a yellow gum (0.5 g, 36%).
Example 120c Preparation of intermediate rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F of0H
N H F. 11 'N:N -Cl F
M. W. 522.39 C24H23C12F2N503.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 120b (0.5 g, 0.86 mmol) was reacted .with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (0.54 g, 96%).
Example 120d Preparation of intermediate rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide Cl F 0 /.1\1-......r-e 0 = NH
c, M. W. 649.57 C31-136C12F2N603 In a manner similar to the method described in Examples 42c, rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 120c (0.54 g, 0.85 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.37 g, 2.54 mmol), HATU (0.58 g, 1.5 mmol) and iPr2NEt (0.74 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylFamide as a light yellow solid (0.5 g, 91%).
Example 120e Preparation of rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F OH
OH
NH
Cl M. W. 609.50 C28H32C12F2N603 In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 120d (40 mg, 0.06 mmol) was reacted with aqueous HC1 solution (1 N, 3 mL, 3 mol) in tetrahydrofuran (7 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (29 mg, 79%).
H R. MS (ES' ) raiz Cated fi,r C28H32C12F2N603 H [(M I 1) ]: 009, 1954, round:
609.1954.
Example 121a Preparation of intermediate rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide 0%, = : NH
101v" NH2 Cl M. W. 623.58 C31-138C12F2N403 In a manner similar to the method described in Examples 118a, rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 120d (0.5 g, 0.77 mmol) was treated with Pt02 and H2 in ethyl acetate to give rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl]-amide as a black gum (0.47 g, 98%) Example 121b Preparation of rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
OH
= NH
W."NH2 CI
M. W. 583.50 C28H34C12F2N403 In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 121a (50 mg, 0.08 mmol) was reacted with aqueous HC1 solution (1 N, 3 mL, 3 mol) in tetrahydrofuran (7 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (29 mg, 62%).
H R. MS (ES' ) rii/z Ca for C281-134C12F2N403 H [( M I i)1: 583.2049, fund:
583.2047.
Example 122a Preparation of intermediate rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide CI F
NH
cl Nric ;N
M. W. 665.61 C33H40C12F2N404 To a solution of rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide (60 mg, 0.096 mmol) prepared in Example 121a and triethylamine (0.033 mL, 0.24 mmol) in tetrahydrofuran (3 mL) was added acetyl chloride (0.08 mL, 0.11 mmol). The reaction mixture was stirred at room temperature for 30 min, then water was added. The mixture was partitioned between ethyl acetate and water.
Organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (2% Me0H in Et0Ac) to give rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide as a off white gum (60 mg, 94%) Example 122b Preparation of rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
OH
= NH
\Sk CI
M. W. 625.54 C30H36C12F2N404 In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide prepared in Example 122a (60 mg, 0.09 mmol) was reacted with aqueous HO
solution (1 N, 1 mL, 1 mol) in tetrahydrofuran (5 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (50 mg, 89%).
FIRMS (ES-) rniz Calcd for C30H36C12F2N404: fl [0,1-F I-I )' j: 625.2155, found: 625.2151.
Example 123 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-methanesulfonylamino-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide =NH OH
C?µ ,0 OP' N \
CI
M. W. 661.59 C29H36C12F2N405S
In a manner similar to the method described in Examples 122a and 122b, rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide (60 mg, 0.096 mmol) prepared in Example 121a was reacted with triethylamine and methanesulfonyl chloride (13 mg, 0.11 mmol) in dichloromethane, followed by the reaction with aqueous HC1 solution in tetrahydrofuran to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(4-methanesulfonylamino-2,2-dimethyl-buty1)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (57 mg, 90%) HRMS (ES `) rniz Calcd idr C29H36C12F2N405S-4- H [(M H)"1: 6611825. found:
661.1821.
Example 124 Preparation of rac-(2R,3S,4R,5S)-5-(4-benzoylamino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
*
: OH
101µ"µ
M. W. 687.61 C35H38C12F2N404 In a manner similar to the method described in Examples 122a and 122b, rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl]-amide (80 mg, 0.13 mmol) prepared in Example 121a was reacted with triethylamine and benzoyl chloride (22 mg, 0.16 mmol) in tetrahydrofuran, followed by the reaction with aqueous HC1 solution in tetrahydrofuran to give rac-(2R,3S,4R,5S)-5-(4-benzoylamino-2,2-dimethyl-buty1)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a off white solid (57 mg, 90%) HRMS (ES') /111Z Calcd for C35H38C12F2N404-E 1-1 [(M+1-1) 1: 687.2311. found:
687.2308 Example 125a Preparation of intermediate [3-methy1-3-(5-methyl-furan-2-y1)-but-(E)-ylideneamino]-acetic acid tert-butyl ester r M. W. 279.38 C16H25NO3 Step A
To a solution of dimethyl malonate (6.5 g, 49 mmol), 2-acetyl-5-methylfuran (6.1 g, 49 mmol) and pyridine (16 g, 200 mmol) in anhydrous tetrahydrofuran (300 mL) at 0 C
was added a dichloromethane solution (1 M) of TiC14 (100 mL, 100 mmol) during a period of 1 h. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 18 h. Water was added to quench the reaction. The mixture was extracted with ethyl ether.
The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;10) to give 2-[1-(5-methyl-furan-2-y1)-ethylidene]-malonic acid dimethyl ester as a yellow oil (3.7 g, 32%).
Step B
To a suspension of CuI (7.61 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) at -50 C was added methylmagnesium chloride (3 M, 27 mL, 80 mmol) during a period of 15 min. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to -50 C, a tetrahydrofuran solution (50 mL) of 241-(5-methyl-furan-2-y1)-ethylidene]-malonic acid dimethyl ester (3.7 g, 15.5 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 3 h. Aqueous saturated NH4C1 solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1:20, 1:10) to give 2[1-methy1-1-(5-methyl-furan-2-y1)-ethyl]-malonic acid dimethyl ester as a colorless oil (2.5 g, 63%).
Step C
To a solution of 2-[1-methy1-1-(5-methyl-furan-2-y1)-ethyl]-malonic acid dimethyl ester (2.5 g, 9.8 mmol) in DMSO (30 mL) was added LiC1 (1 g, 23.7 mmol) and H20 (0.17 mL, 9.8 mmol).
The reaction mixture was heated at 170 C for 3 h, then poured into a ice-water, extracted with ethyl acetate. The organic layer were separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1:20, 1:20) to give 3-methyl-3-(5-methyl-furan-2-y1)-butyric acid methyl ester as a colorless oil (1.5 g, 78%).
Step D
To a solution of 3-methy1-3-(5-methyl-furan-2-y1)-butyric acid methyl ester (1.5 g, 7.8 mmol) in anhydrous tetrahydrofuran (50 mL) at 0 C was added a tetrhydrofuran solution (1 M) of LiAlF14 (10 mL, 10 mmol) under nitrogen. The reaction mixture was stirred at 0 C for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated to give 3-methy1-3-(5-methyl-furan-2-y1)-butan-1-ol as a yellow oil (1.2 g, 77%).
Step E
To a solution of oxalyl chloride (0.91 g, 7.1 mmol) (Aldrich) in dichloromethane (20 mL) at -78 C was added the solution of dimethyl sulfoxide (1 mL, 14.3 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 3-methy1-3-(5-methyl-furan-2-y1)-butan-l-ol (1.2 g, 7.1 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (3.6 mL, 26 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3-methy1-3-(5-methyl-furan-2-y1)-butyraldehyde as a yellow oil (Yield: 1 g, 83%).
Step F
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.79 g, 6 mmol) was reacted vviih 3-methyl-3-(5-methyl-furan-2-y1)-butyraldehyde (i g, o mmoi) in CH2C12 at room temperature for 5 h to give [3-methy1-3-(5-methyl-furan-2-y1)-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.7 g, 100%).
Example 125b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-y1)-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester CI F
= NH
I
M. W. 589.52 C31H32C12F2N203 In a manner similar to the method described in Example 100b, [[3-methy1-3-(5-methyl-furan-2-y1)-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 125a (1.7 g, 6 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (1.48 g, 4.8 mmol) prepared in Example 52a, AgF (0.9 g, 7 mmol), and triethylamine (1.7 mL, 12 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (5.7 ml) in tert-butanol (10 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-y1)-propy1]-pyrrolidine-2-carboxylic acid tert-butyl ester as a yellow solid (1.3 g, 46%).
Example 125c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-(2,2-diethyl-buty1)-pyrrolidine-2-carboxylic acid trifluoroacetic acid Cl F
= NH
F. 11 FOH
M. W. 533.41 C27H24C12F2N203.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-542-methyl-2-(5-methyl-furan-2-y1)-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 125b (1.3 g, 2.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-y1)-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a brown solid (1.3 g, 92%).
Example 125d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-y1)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
OH
= NH
Cl FN /
M. W. 620.52 C311133C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-y1)-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 125c (0.6 g, 0.93 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.4 g, 2.8 mmol), HATU (0.6 g, 1.7 mmol) and iPr2NEt (0.8 mL, 4.6 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-y1)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.16 g, 29%).
HRMS (ES) `)milz Caled for C3 H33 Cl2F2N3 04+ H [(1\,4+1-1) ]: 620.1889, found: 620.1889.
Example 126a Preparation of intermediate [4-(4-methoxy-phenyl)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid methyl ester OTO.
M. W. 277.37 C16H23NO3 Step A.
Under Argon, a mixture of NaOH (2.8 g, 70 mmol),tetrabutylammonium iodide (0.6 g, 1.6 mmol) in benzene (8 mL) and H20 (2.8 mL) was heated at 70 C to form a homogeneous mixture. A mixture of 4-methoxybenzyl chloride (Aldrich) (10 g, 64 mmol) and isobutyraldehyde (5.76 g, 80 mmol) in benzene (22 mL) was added dropwise. The resulting reaction mixture was heated at 70 C for 3 h. The mixture was cooled, extracted with ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate.
The organic layers were combined, concentrated. The residue was purifed by chromatography (Et0Ac:hexanes=1;30) to give 2-(4-methoxy-phenyl)-2-methyl-propionaldehyde as a colorless oil (4.1 g, 33%).
Step B
To a mixture of methoxymethyl triphenylphosphonium chloride (14.6 g, 42 mmol) in anhydrous tetrahydrofuran (60 mL) at 0 C was a tetrahydrofuran solution (Aldrich, 1 M) of LiHMDS (42 mL, 42 mmol) dropwise. After the addition was finished, the reaction mixture was stirred at 0 C
for 20 min. Then a tetrahydrofuran solution (40 mL) of 2-(4-methoxy-pheny1)-2-methyl-propionaldehyde (4.1g, 21 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 1 h. Water was added to quench the reaction. The mixture was extracted with ethyl acetate twice. The organic layers were combined, concentrated.
The residue was purifed by chromatography (Et0Ac:hexanes=1:30, 1:20) to give a yellow oil (3.5 g). The oil was dissolved into a solution of aqueous HC1 solution (2 N, 50 mL, 100 mmol) and tetrahydrofuran (50 mL). The reaction mixture was heated at reflux for 1 h, then cooled to room temperature and concentrated. The residue partitioned between ethyl acetate and water.
The organic layer was separated, concentrated. The residue was purified by chromatography (Et0Ac:hexanes=1:10,1:5) to give 3-(4-methoxy-phenyl)-3-methyl-butyraldehyde as a colorless oil (2.1 g, 47%).
Similar transformations have been reported in US6531494 and the procedures described were used without modifications.
Step C
In a manner similar to the method described in Example la, glycine methyl ester hydrochloride (1.25 g, 10 mmol) was reacted with 3-(4-methoxy-phenyl)-3-methyl-butyraldehyde (2.1 g, 10 mniol) and triethyIarnine (2.2 g. 20 nlimo I) in CH2C12 at room temperature for 5 h to give [4-(4-methoxy-pheny1)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid methyl ester as a colorless oil (2.7 g, 97%).
Example 126b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[3-(4-methoxy-pheny1)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid methyl ester CI F
= NH
sor *
CI FN
M. W. 587.50 C31-130C12F2N203 In a manner similar to the method described in Example lc, [4-(4-methoxy-pheny1)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid methyl ester prepared in Example 126a (2.7 g, 9.7 mmol) was v.:acted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (3.1 g, 10 mmol) prepared in Example 52a, AgF (1.27 g, 10 mmol), and triethylamine (6 g, 60 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[3-(4-methoxy-pheny1)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid methyl ester as a yellow solid (4 g, 70%).
Example 126c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[3-(4-methoxy-pheny1)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid Ci F0/OH
= NH
0.
CI FN
M. W. 573.47 C30H28C12F2N203 To rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-543-(4-methoxy-pheny1)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid methyl ester prepared in Example 126b (4 g, 6.8 mmol) in tetrahydrofuran (60 mL) was added an aqueous solution (1 N) of NaOH (20 mL, 20 mmol) and methanol (20 mL). The reaction mixture was stirred at room temperature for 3 h. The "pH" of the mixture was adjusted to ¨4-5 by aqueous HC1 solution. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over Mg504, concentrated to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-pheny1)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid as a light yellow solid (4 g, 100%) Example 126d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[3-(4-methoxy-pheny1)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
OH
NH
CI
M. W. 660.59 C34H37C12F2N304 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[3-(4-methoxy-pheny1)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid prepared in Example 126c (0.5 g, 0.87 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.25 g, 1.7 mmol), HATU (0.6 g, 1.7 mmol) and iPr2NEt (0.45 mL, 2.6 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[3-(4-methoxy-pheny1)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.16 g, 29%).
FIRMS (ES') ITLIZ Cale' for C34H37C12F2N304--E 1-1 [(M+f-Ea 660.2202. found:
660.2198.
Example 127a Preparation of intermediate [3-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester I
M. W. 370.54 C23/{34N202 Step A
To a tetrahydrofuran solution (Aldrich, 1.8 M) of LDA (60 mL, 109 mmol) at -50 C was added isobutyric acid ethyl ester (Alfa) (12.2 mL, 91 mmol) dropwise. The reaction mixture was stirred -50 C for 1 h, then a tretrahydrofuran solution (10 mL) of 1-benzyl-piperidin-4-one (12 mL, 68 mmol) was added dropwise. The reaction mixture was warmed up to room temperature and stirred for 18 h. Aqueous saturated NH4C1was added to quench the reaction. The mixture was extracted with ethyl ether. The organic layer was separated, and the aqueous layer was extracted with ethyl ether. The organic layers were combined, washed with brine, water, dried over MgSO4, and concentrated to give 2-(1-benzy1-4-hydroxy-piperidin-4-y0-2-methyl-propionic acid ethyl ester as an orange oil (18.5 g, 89%).
Step B
To a solution of 2-(1-benzy1-4-hydroxy-piperidin-4-y1)-2-methyl-propionic acid ethyl ester (18.5 g, 61 mmol) in chloroform (75 mL) was added thionyl chloride (8.9 mL, 120 mmol) and dimethylformamide (0.17 mL). The reaction mixture was heated at 100 C for 18 h, then cooled to room temperature and concentrated. To the resulting residue was added aqueous NaOH
solution (10 N) to adjust the "pH" of the mixture to basic. The mixture was then extracted with ethyl ether twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give 2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propionic acid ethyl ester as a brown oil (13 g, 75%).
Step C
To a solution of 2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propionic acid ethyl ester (6 g, 21 mmol) in anhydrous tetrahydrofuran 75 mL) at 0 C was added a tetrhydrofuran solution (1 M) of LiA1H4 (84 mL, 84 mmol) under nitrogen. The reaction mixture was heated at reflux for 3 h, then cooled to room temperature. Water and aqueous NaOH solution (2N) was added. The mixture was filtered to remove the precipitate, and the filtrate was concentrated. Water was added, and the mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated to give 2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propan-1-ol as a brown oil (4.73 g, 77%).
Step D
To a solution of oxalyl chloride (2.46 mL, 28 mmol) (Aldrich) in dichloromethane (150 mL) at -78 C was added the solution of dimethyl sulfoxide (4 mL, 56 mmol) in dichloromethane (25 mL) dropwise. After 5 mins, the solution of 2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propan-1-ol (6.3 g, 25.6 mmol) in dichloromethane (25 mL) was added dropwise.
The reaction mixture was stirred at -78 C for 15 min. Triethylamine (12.8 mL, 92 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 241-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propionaldehyde as a brown oil (Yield: 5.6 g, 89%).
Step E
To a mixture of methoxymethyl triphenylphosphonium chloride (12.6 g, 37 mmol) in anhydrous tetrahydrofuran (50 mL) at 0 C was a tetrahydrofuran solution (Aldrich, 1 M) of LiHMDS (46 mL, 46 mmol) dropwise. After the addition was finished, the reaction mixture was stirred at 0 C
for 20 min. Then a tetrahydrofuran solution (40 mL) of 2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propionaldehyde (5.6 g, 23 mmol) was added. The reaction mixture was stirred at 0 C for 2 h. Water was added to quench the reaction. The mixture was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was dissolved into a solution of aqueous HC1 solution (2 N, 50 mL, 100 mmol) and tetrahydrofuran (50 mL). The reaction mixture was heated at reflux for 30 min, then cooled to room temperature and concentrated. The residue partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by chromatography (Et0Ac:hexanes=1:3) to give 3-0 -bonzy1-1,2,3,6-teftahydro-pyridin-4-0-3-1m.thyl-butyraidehyde as a yellow oil (1.65 g, 28%).
Step F
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.84 g, 6.4 mmol) was reacted with 3-( 1 -berizyi-1,2,3,6-tetrahydro-pyridin-4-y1 )-3-methyl-butyra ide1/2,rde (1.65 g, 6.4 Inmo I) in CH2C12 at room temperature for 5 h to give [3-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (2.4 g, 100%).
Example 127b Preparation of intermediate rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-343-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester CI
NH
CI F ¨ µ N =
M. W. 680.67 C381-141C12F2N303 In a manner similar to the method described in Example 100b, [3-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 127a (2.4 g, 6.4 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.8 g, 6.4 mmol) prepared in Example 52a, AgF (1.3 g, 10 mmol), and triethylamine (2 mL, 14.5 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (7 ml) in tert-butanol (30 mL) at 100 C for 2 h to give rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow solid (3.2 g, 81%).
Example 127e Preparation of intermediate rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid Ci F OH
= NH
F. 11 µ'%
CI FN N
M. W. 626.58 C34H35C12F2N303.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 127b (1.5 g, 2.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (1.6 g, 98%).
Example 127d Preparation of intermediate rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide CI F
= NH
CI FN N *
M. W. 751.75 C41H46C12F2N403 In a manner similar to the method described in Examples 42c, rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 127c (1.6 g, 2.2 mmol) was reacted with 24(S)-2,2-dimethy141,3]dioxolan-4-y1)-ethylamine (0.94 g, 6.5 mmol), HATU (2.5 g, 6.5 mmol) and iPr2NEt (2.3 mL, 13 mmol) in CH2C12 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide as a light yellow gum (1 g, 83%).
Example 127e Preparation of rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1 ,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
=OH
NH
Cl FN / N *
M. W. 711.68 C38H42C12F2N403 In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl]-amide prepared in Example 127d (1 g, 1.3 mmol) was reacted with aqueous HC1 solution (1 N, 5 mL, 5 mol) in tetrahydrofuran (5 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propyl]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 32%).
FIRMS (ES )1/1/z Caled for C38H42C12F2N403 II [0,114-1)' j: '711.2675, found:
71 1.2675, Example 128 Preparation of rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-piperidin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI F
,NH OH
CI \\N
N *
M. W. 713.69 C38I-144C12F2N403 In a manner similar to the method described in Examples 118a, rac-(2R,3S,4R,55)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide prepared in Example 127e (60 mg, 0.08 mmol) was treated with Pt02 and H2 in ethyl acetate to give rac-(2R,3S,4R,5S)-542-(1-benzyl-piperidin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a off white solid (15 mg, 25%) FIRMS (ES) miz Calf:A for C38H44C12F2N4034- 11 [(M11-1) j: 713.2832, (bund:
713.2837, Example 129a Preparation of intermediate [3-(3,6-dihydro-2H-pyran-4-y1)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester I
M. W. 281.40 C16H27NO3 Step A
To a hexane solution (Aldrich, 2 M) of LDA (78 mL, 160 mmol) in tetrahydrofuran (100 mL) at -50 C was added a solution of isobutyric acid ethyl ester (Alfa) (17 mL, 127 mmol) in tetrahydrofuran (20 mL) dropwise. The reaction mixture was stirred -50 C for 1 h, then a tretrahydrofuran solution (10 mL) of tetrahydro-pyran-4-one (Aldrich) (9.8 g, 98 mmol) was added dropwise. The reaction mixture was warmed up to room temperature and stirred for 18 h.
Aqueous saturated NH4C1was added to quench the reaction. The mixture was extracted with ethyl ether. The organic layer was separated, and the aqueous layer was extracted with ethyl ether. The organic layers were combined, washed with brine, water, dried over MgSO4, and concentrated to give 2-(4-hydroxy-tetrahydro-pyran-4-y1)-2-methyl-propionic acid ethyl ester as a yellow oil (19.5 g, 92%).
Step B
To a solution of 2-(4-hydroxy-tetrahydro-pyran-4-y1)-2-methyl-propionic acid ethyl ester (19.5 g, 90 mmol) in chloroform (100 mL) was added thionyl chloride (13.3 mL, 180 mmol) and dimethylformamide (0.28 mL). The reaction mixture was heated at 100 C for 18 h, then cooled to room temperature and concentrated. To the resulting residue was added aqueous NaOH
solution (10 N) to adjust the "pH" of the mixture to basic. The mixture was then extracted with ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give 2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propionic acid ethyl ester as a brown oil (17.6 g, 99%).
Step C
To a solution of 2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propionic acid ethyl ester (6 g, 30 mmol) in anhydrous tetrahydrofuran (75 mL) at 0 C was added a tetrhydrofuran solution (1 M) of LiA1H4 (100 mL, 100 mmol) under nitrogen. The reaction mixture was heated at reflux for 3 h, then cooled to room temperature. Water and aqueous NaOH solution (2N) was added. The mixture was filtered to remove the precipitate, and the filtrate was concentrated. Water was added, and the mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSO4, and concentrated to give 2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propan-1-ol as a brown oil (4.63 g, 98%).
Step D
To a solution of oxalyl chloride (2.84 mL, 33 mmol) (Aldrich) in dichloromethane (150 mL) at -78 C was added the solution of dimethyl sulfoxide (4.6 mL, 65 mmol) in dichloromethane (25 mL) dropwise. After 5 mins, the solution of 2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propan-1-ol (4.6 g, 29 mmol) in dichloromethane (25 mL) was added dropwise. The reaction mixture was stirred at -78 C for 15 min. Triethylamine (14.8 mL, 110 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min.
Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propionaldehyde as a brown oil (Yield: 5.6 g, 89%).
Step E
To a mixture of methoxymethyl triphenylphosphonium chloride (31.3 g, 91 mmol) in anhydrous tetrahydrofuran (150 mL) at 0 C was a tetrahydrofuran solution (Aldrich, 1 M) of LiHMDS (110 mL, 110 mmol) dropwise. After the addition was finished, the reaction mixture was stirred at 0 C for 20 min. Then a tetrahydrofuran solution (40 mL) of 2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propionaldehyde (4.4 g, 28.5 mmol) was added. The reaction mixture was stirred at 0 C
for 1 h. Water was added to quench the reaction. The mixture was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was dissolved into a solution of aqueous HC1 solution (2 N, 50 mL, 100 mmol) and tetrahydrofuran (50 mL). The reaction mixture was heated at reflux for 30 min, then cooled to room temperature and concentrated. The residue partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by chromatography (Et0Ac:hexanes=1:3) to give 3-(3,6-dihy,iro-211-pyran-4-yi)-3-methy1-bulyra1dehytie as a brown oil (2.61 g, 54%).
Step F
In a manner similar to the method described in Example la, glycine tert-butyl ester (2 g, 15.5 mmol) was reacted wiLl/ 3-(3,6-dillydro-2ii-pyran-4-y1)-3-lneihyl-butyralciellyde (2.6 g. 15.5 minol) in CH2C12 at room temperature for 5 h to give [3-(3,6-dihydro-2H-pyran-4-y1)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (4.3 g, 100%).
Example 129b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propy1]-pyrrolidine-2-carboxylic acid tert-butyl ester CI Fle0-..K...
:H
M. W. 591.53 C31H34C12F2N203 In a manner similar to the method described in Example 100b, [3-(3,6-dihydro-2H-pyran-4-y1)-3-methyl-but-(E)-ylideneamincfl-acetic acid tert-butyl ester prepared in Example 129a (4.3 g, 15.5 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-pheny1)-2-(4-chloro-2-fluoro-pheny1)-acrylonitrile (3.8 g, 12.4 mmol) prepared in Example 52a, AgF (2.4 g, 19 mmol), and triethylamine (4.3 mL, 31mmo1) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (19 ml) in tert-butanol (18 mL) at 100 C
for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propy1]-pyrrolidine-2-carboxylic acid tert-butyl ester as a yellow gum(5.5 g, 75%).
Example 129c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid CI F
= NH
F
M. W. 535.42 C27H26C12F2N303.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-542-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 129b (5.5 g, 9.29 mmol) was rcacted v./id/ trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a dark solid (6 g, 99%).
Example 129d Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propy1]-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethy1]-amide Cl F
= NH
CI F µµN I 0 M. W. 662.61 C34H39C12F2N304 In a manner similar to the method described in Examples 42c, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-542-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 129c (0.8 g, 1.2 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethylamine (0.36 g, 2.5 mmol), HATU (0.84 g, 2.2 mmol) and iPr2NEt (0.64 mL, 3.7 mmol) in CH2C12 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-5-[2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propy1]-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-pyrrolidine-2-carboxylic acid [24(S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl]-amide as a off white gum (0.6 g, 74%).
Example 129e Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propy1]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide CI F
OH
NH
CI F \\N I 0 M. W. 622.54 C31H35C12F2N304 In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-542-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propy1]-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-y1)-ethyl]-amide prepared in Example 129d (0.6 g, 0.9 mmol) was reacted with aqueous HC1 solution (1 N, 3 mL, 3 mol) in tetrahydrofuran (7 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a white solid (0.52 g, 93%).
FIRMS (ES) mlz Caled for C31H35C12F2N3O4 1 [(M j: 622.2046, found:
622.2046.
Example 130 Preparation of rac-(2R,3S,4R,5S)-3-(3-hloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(tetrahydro-pyran-4-y1)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide CI F
NH OH
M. W. 624.55 C311-13702F2N304 In a manner similar to the method described in Examples 118a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-542-(3,6-dihydro-2H-pyran-4-y1)-2-methyl-propy1]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide prepared in Example 127e (0.28 g, 0.45 mmol) was treated with Pt02 and H2 in ethyl acetate to give rac-(2R,3S,4R,5S)-3-(3-hloro-2-fluoro-pheny1)-4-(4-chloro-2-fluoro-pheny1)-4-cyano-5-[2-methyl-2-(tetrahydro-pyran-4-y1)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-buty1)-amide as a off white solid (0.15 g, 54%) FIRP,AS (ES `) Cal ed for C311-13702F2N304: j: 624.2202, found: 624.2207.
Example 131a Preparation of intermediate 2-((S)-2,2,5,5-ttramethyl-[1,3]dioxolan-4-y1)-ethylamine H2N,/"---X0 0¨ft M. W. 173.26 C9H19NO2 Step A.
To a suspension of L-(-)-malic aicd (Aldrich) (10.3 g, 77 mmol) in 2,2-dimethoxypropane (20 mL) was added p-toluenesulfonic acid monohydrate (0.4 g). The reaction mixture was stirred at room temperature for 30 min. The mixture was partitioned between water and dichloromethane.
The organic layer was separated, the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated to give ((S)-2,2-dimethy1-5-oxo-[1,3]dioxolan-4-y1)-acetic acid as a white solid (10.1 g, 75%).
Step B
To the solution of ((S)-2,2-dimethy1-5-oxo-[1,3]dioxolan-4-y1)-acetic acid (10.1 g, 58 mmol) in anhydrous tetrahydrofuran (20 mL) at 0 C was added a solution of BH3.THF (1 M, 70 mL, 70 mmol). The reaction mixture was stirred at room temperature for 2 h. Aqueous HC1 solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated.
The residue was purified by chromatography (Et0Ac) to give (S)-5-(2-hydroxy-ethyl)-2,2-dimethyl-[1,3]dioxolan-4-one as a colorless oil (6.8 g, 72%).
Step C
A mixture of (S)-5-(2-hydroxy-ethyl)-2,2-dimethyl-[1,3]dioxolan-4-one (6.8 g, 42 mmol) and imidazole (7.5 g, 107 mmol) in dimethylformamide (40 mL) was added tert-butyldimethylchlorosilane (7 g, 45 mmol). The reactiom mixture was stirred at room temperature for 18 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl acetate twice. The combined organic layers wer washed with brine, dried over MgSO4, concentrated to give (S)-542-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2,2-dimethyl-[1,3]dioxolan-4-one as a colorless oil (8.6 g, 74%).
Step D
To a solution of (S)-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethy1]-2,2-dimethyl-[1,3]dioxolan-4-one (8.5 g, 31 mmol) in diethyl ether (200 mL) at 0 C was added a diethyl ether (1.6 M) solution of methyllithium (50 mL, 78 mmol) dropwise. The reaction mixture was stirred at 0 C for 30 min. The mixture was poured into aqueous saturated NH4C1 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to give (S)-5-(tert-butyl-dimethyl-silanyloxy)-2-methyl-pentane-2,3-diol as a yellow oil (Yield: 6.8 g, 88%).
Step E
To a suspension of (S)-5-(tert-butyl-dimethyl-silanyloxy)-2-methyl-pentane-2,3-dio1 (6.8 g, 27 mmol) in 2,2-dimethoxypropane (35 mL) was added p-toluenesulfonic acid monohydrate (0.2g).
The reaction mixture was stirred at room temperature for 30 min. The mixture was partitioned between water and dichloromethane. The organic layer was separated, the aqueous layer was DEMANDES OU BREVETS VOLUMINEUX
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Claims (343)
1. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide.
2. The compound:
(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide.
(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide.
3. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid dimethylamide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid dimethylamide.
4. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
5. The compound:
(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
6. The compound:
rac-(2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile.
rac-(2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile.
7. The compound:
rac-(25,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile.
rac-(25,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile.
8. The compound:
rac-(2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile.
rac-(2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile.
9. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydroxy-butyl)-amide.
10. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide.
11. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-piperazin-1-yl-ethyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-piperazin-1-yl-ethyl)-amide.
12. The compound:
(S)-2- { [(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid methyl ester.
(S)-2- { [(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid methyl ester.
13. The compound:
(S)-2-{ [(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid.
(S)-2-{ [(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid.
14. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclopropylmethyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclopropylmethyl)-amide.
15. The compound:
rac-(2R,3R,4R,5S)-3-(3-Chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclobutylmethyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-Chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclobutylmethyl)-amide.
16. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl) pyrrolidine-2-carboxylic acid (3,3-dimethyl-butyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl) pyrrolidine-2-carboxylic acid (3,3-dimethyl-butyl)-amide.
17. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2,2-dimethyl-propyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2,2-dimethyl-propyl)-amide.
18. The compound:
(2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-((S)-2-hydroxymethyl-pyrrolidine-1-carbonyl) pyrrolidine-3-carbonitrile.
(2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-((S)-2-hydroxymethyl-pyrrolidine-1-carbonyl) pyrrolidine-3-carbonitrile.
19. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-(3,4-dimethoxy-phenyl)ethyl amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-(3,4-dimethoxy-phenyl)ethyl amide.
20. The compound:
(2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-1-hydroxymethyl-3-methyl-butyl)-amide.
(2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-1-hydroxymethyl-3-methyl-butyl)-amide.
21. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide.
22. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(cis-2,6-dimethyl-morpholin-4-yl)-ethyl]-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(cis-2,6-dimethyl-morpholin-4-yl)-ethyl]-amide.
23. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-cyclopropyl-ethyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-cyclopropyl-ethyl)-amide.
24. The compound:
rac-(3-{ [(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester.
rac-(3-{ [(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester.
25. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide.
26. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1-acetyl-piperidin-4-ylamino)-propyl]-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1-acetyl-piperidin-4-ylamino)-propyl]-amide.
27. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide.
28. The compound:
rac-(2R,3R,4R,5R)-5-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide.
rac-(2R,3R,4R,5R)-5-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide.
29. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide.
30. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
31. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide.
32. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxyl ic acid (3-hydroxy-2,2-dimethyl-propyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxyl ic acid (3-hydroxy-2,2-dimethyl-propyl)-amide.
33. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide.
34. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-acetylamino-ethyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-acetylamino-ethyl)-amide.
35. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-imidazol-1-yl-propyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-imidazol-1-yl-propyl)-amide.
36. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-4-hydroxy-3-methyl-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-4-hydroxy-3-methyl-butyl)-amide.
37. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid cyclopropylmethoxy-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid cyclopropylmethoxy-amide.
38. The compound:
rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [24(S)-2,2-dimethyl41,3]dioxolan-4-yl)-ethyl]-amide.
rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [24(S)-2,2-dimethyl41,3]dioxolan-4-yl)-ethyl]-amide.
39. The compound:
rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
40. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
41. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyI)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyI)-amide.
42. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
43. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
44. The compound:
rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
45. The compound:
rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
46. The compound:
rac-(2R,3R,4R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
47. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
48. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
49. The compound:
rac-(2R,3S,4R,5S)-5-tert-butyl-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-5-tert-butyl-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
50. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
51. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
52. The compound:
rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
53. The compound:
rac-(2R,3S,4R,5S)-4-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-4-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
54. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
55. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
56. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
57. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyI)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyI)-amide.
58. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
59. The compound:
rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
60. The compound:
rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyI)-amide.
rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyI)-amide.
61. The compound:
(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
62. The compound:
rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyI)-amide.
rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyI)-amide.
63. The compound:
(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
64. The compound:
rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
65. The compound:
(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
66. The compound:
rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
67. The compound:
rac-(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
68. The compound:
rac-(25,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(25,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
69. The compound:
rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(3,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(3,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
70. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
71. The compound:
(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
72. The compound:
rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-yl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-yl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
73. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
74. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
75. The compound:
(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
76. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
77. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
78. The compound:
rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
79. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
80. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
81. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
82. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
83. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide.
84. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
85. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
86. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
87. The compound:
rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
88. The compound:
rac(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (quinolin-3-ylmethyl)-amide.
rac(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (quinolin-3-ylmethyl)-amide.
89. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-hydroxy-benzylamide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-hydroxy-benzylamide.
90. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-ethyl-butyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-ethyl-butyl)-amide.
91. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
92. The compound:
rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-[5-chloro-2-(2-hydroxy-ethoxy)-phenyl]-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-[5-chloro-2-(2-hydroxy-ethoxy)-phenyl]-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
93. The compound:
rac-4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester.
rac-4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester.
94. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic acid.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic acid.
95. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-methanesulfonylpiperidin-4-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-methanesulfonylpiperidin-4-yl)-amide.
96. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-methyl-carbonyl-piperidin-4-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-methyl-carbonyl-piperidin-4-yl)-amide.
97. The compound:
rac-(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-benzoyl-piperidin-4-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-benzoyl-piperidin-4-yl)-amide.
98. The compound:
rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-piperidine-1-carboxylic acid isopropylamide.
rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-piperidine-1-carboxylic acid isopropylamide.
99. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide.
100. The compound:
chiral 2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide.
chiral 2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide.
101. The compound:
chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide.
chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide.
102. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide.
103. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((R)-3-amino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((R)-3-amino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide.
104. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-{2-[(R)-2-hydroxy-3-(3-hydroxy-propylamino)-propoxy]-2-methyl-propyl}-1H-pyrazol-3-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-{2-[(R)-2-hydroxy-3-(3-hydroxy-propylamino)-propoxy]-2-methyl-propyl}-1H-pyrazol-3-yl)-amide.
105. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-{2-[(R)-2-hydroxy-3-(2-hydroxy-1-hydroxymethyl-ethylamino)-propoxy]-2-methyl-propyl}-1H-pyrazol-3-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-{2-[(R)-2-hydroxy-3-(2-hydroxy-1-hydroxymethyl-ethylamino)-propoxy]-2-methyl-propyl}-1H-pyrazol-3-yl)-amide.
106. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid{1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl} -amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid{1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl} -amide.
107. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-3-amino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-3-amino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide.
108. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-2,3-dihydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-2,3-dihydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide.
109. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl)-amide.
110. The compound:
rac-{(S)-3 -[2-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-yl)-1,1-dimethyl-ethoxy]-2-hydroxy-propylamino}-acetic acid.
rac-{(S)-3 -[2-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-yl)-1,1-dimethyl-ethoxy]-2-hydroxy-propylamino}-acetic acid.
111. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)pyrrolidine-2-carboxylic acid {1-[2-((S-2-hydroxy-3-methylamino-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)pyrrolidine-2-carboxylic acid {1-[2-((S-2-hydroxy-3-methylamino-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide.
112. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid{1-[2-((R)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid{1-[2-((R)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl)-amide.
113. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide.
114. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-amide.
115. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-2,3-dihydroxy-propyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-2,3-dihydroxy-propyl)-amide.
116. The compound:
rac-(2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-2,3-dihydroxy-propyl)-amide.
rac-(2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-2,3-dihydroxy-propyl)-amide.
117. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide.
118. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-trifluoromethyl-benzylamide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-trifluoromethyl-benzylamide.
119. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-(2-oxo-pyrrolidin-1-yl)-benzylamide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-(2-oxo-pyrrolidin-1-yl)-benzylamide.
120. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide.
121. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-2-hydroxymethyl-propyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-2-hydroxymethyl-propyl)-amide.
122. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(2-amino-ethoxy)-ethyl]-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(2-amino-ethoxy)-ethyl]-amide.
123. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfonyl-propyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfonyl-propyl)-amide.
124. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-methanesulfonyl-ethyl)-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-methanesulfonyl-ethyl)-amide.
125. The compound:
rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino-cyclohexylamino-1-carboxylic acid tert-butyl ester.
rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino-cyclohexylamino-1-carboxylic acid tert-butyl ester.
126. The compound:
rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5 -(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-trans-cyclohexylamine trifluoroacetic acid salt.
rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5 -(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-trans-cyclohexylamine trifluoroacetic acid salt.
127. The compound:
rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2 -fluoro-phenyl)-4 -cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-trans-cyclohexyl-N-methanesulfonamide.
rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2 -fluoro-phenyl)-4 -cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-trans-cyclohexyl-N-methanesulfonamide.
128. The compound:
rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-trans-cyclohexyl-(1,1-dioxo)-2-isothiazolidine.
rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-trans-cyclohexyl-(1,1-dioxo)-2-isothiazolidine.
129. The compound:
rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-trans-cyclohexyl-urea.
rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-trans-cyclohexyl-urea.
130. The compound:
rac(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid N-[1-(2-hydroxy ethyl)-piperidin-4-yl]amide.
rac(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid N-[1-(2-hydroxy ethyl)-piperidin-4-yl]amide.
131. The compound:
rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-piperidine-1-sulfonic acid amide.
rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-piperidine-1-sulfonic acid amide.
132. The compound:
rac 3-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-1-yl}-acetic acid.
rac 3-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-1-yl}-acetic acid.
133. The compound:
rac 3-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-1-yl}- N,N-bis-(2-methoxy-ethyl)-acetamide.
rac 3-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-1-yl}- N,N-bis-(2-methoxy-ethyl)-acetamide.
134. The compound:
rac 3-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-1-yl}-N,N-bis-(2-hydroxy-ethyl)-acetamide.
rac 3-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-1-yl}-N,N-bis-(2-hydroxy-ethyl)-acetamide.
135. The compound:
rac 3-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-1-yl - N-( 3-methoxy-propyl)-acetamide.
rac 3-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-1-yl - N-( 3-methoxy-propyl)-acetamide.
136. The compound:
rac 2-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-1-yl} -acetamide.
rac 2-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-1-yl} -acetamide.
137. The compound:
rac (2S,3R,4S,5R)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-morphoIin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile.
rac (2S,3R,4S,5R)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-morphoIin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile.
138. The compound:
rac 2-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-1-yl}-N-[2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-acetamide.
rac 2-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-1-yl}-N-[2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-acetamide.
139. The compound:
rac 2-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-1-yl}-N-((S)-3,4-dihydroxy-butyl)-acetamide.
rac 2-{4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-1-yl}-N-((S)-3,4-dihydroxy-butyl)-acetamide.
140. The compound:
rac 11-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-acetic acid methyl ester.
rac 11-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-acetic acid methyl ester.
141. The compound:
rac {1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-acetic acid hydrochloride salt.
rac {1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-acetic acid hydrochloride salt.
142. The compound:
rac 2-{1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-acetamide.
rac 2-{1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-acetamide.
143. The compound:
rac 2-{1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-N,N-bis-(2-hydroxy-ethyl)-acetamide.
rac 2-{1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-N,N-bis-(2-hydroxy-ethyl)-acetamide.
144. The compound:
rac 2-{1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro 2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-N-(2-hydroxy-ethyl)-N-methyl-acetamide.
rac 2-{1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro 2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-N-(2-hydroxy-ethyl)-N-methyl-acetamide.
145. The compound:
rac 2-{1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-N-(2-hydroxy-propyl)-acetamide.
rac 2-{1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-N-(2-hydroxy-propyl)-acetamide.
146. The compound:
rac {[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-acetic acid tert-butyl ester.
rac {[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-acetic acid tert-butyl ester.
147. The compound:
rac {[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-acetic aid trifluoro acetic acid salt.
rac {[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-acetic aid trifluoro acetic acid salt.
148. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid carbamoylmethyl-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid carbamoylmethyl-amide.
149. The compound:
R2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -acetic aid trifluoro acetic acid salt.
R2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -acetic aid trifluoro acetic acid salt.
150. The compound:
rac 3- { [(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid ethyl ester.
rac 3- { [(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid ethyl ester.
151. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-carbamoyl-phenyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-carbamoyl-phenyl)-amide.
152. The compound:
rac 3- {[(2R,3 S,4R,5 S)-3-(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid tert-butyl ester.
rac 3- {[(2R,3 S,4R,5 S)-3-(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid tert-butyl ester.
153. The compound:
rac 3- {[(2R,3 S,4R,5 S)-3 -(3-chloro-2-fluoro-phenyl)-4-(4 -chloro-2-fluoro-phenyl)-4-cyano-5-(2,2 -dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid.
rac 3- {[(2R,3 S,4R,5 S)-3 -(3-chloro-2-fluoro-phenyl)-4-(4 -chloro-2-fluoro-phenyl)-4-cyano-5-(2,2 -dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid.
154. The compound:
rac (2 R,3 S,4R,5 S)-3-(3 -chloro -2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4 -cyano-5-(2 ,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxymethyl-phenyl)-amide.
rac (2 R,3 S,4R,5 S)-3-(3 -chloro -2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4 -cyano-5-(2 ,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxymethyl-phenyl)-amide.
155. The compound:
rac (3- { [(2R,3 S,4R, 5 S)-3 -(3 -chloro-2-fluoro -phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5 -(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester.
rac (3- { [(2R,3 S,4R, 5 S)-3 -(3 -chloro-2-fluoro -phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5 -(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester.
156. The compound:
rac (2R,3 S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide.
rac (2R,3 S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide.
157. The compound:
rac (2R,3 S,4R,5 S)-3-(3 -chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4 -cyano-5 -(2,2 -dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(aminosulfonyl- amino)-propyl)-amide.
rac (2R,3 S,4R,5 S)-3-(3 -chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4 -cyano-5 -(2,2 -dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(aminosulfonyl- amino)-propyl)-amide.
158. The compound:
rac 2- { [(2R,3 S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid tert-butyl ester.
rac 2- { [(2R,3 S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid tert-butyl ester.
159. The compound:
rac 4- { [(2R,3 S, 4R, 5 S)-3-(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2 -dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid tert-butyl ester.
rac 4- { [(2R,3 S, 4R, 5 S)-3-(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2 -dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid tert-butyl ester.
160. The compound:
rac 4- { [(2R,3 S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid ethyl ester.
rac 4- { [(2R,3 S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid ethyl ester.
161. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-carbamoyl-phenyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-carbamoyl-phenyl)-amide.
162. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-phenyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-phenyl)-amide.
163. The compound:
rac 2-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid ethyl ester.
rac 2-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid ethyl ester.
164. The compound:
rac 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.
rac 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.
165. The compound:
rac 2-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.
rac 2-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.
166. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-cyano-phenyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-cyano-phenyl)-amide.
167. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide.
168. The compound:
rac 3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid 2-hydroxy-2-methyl-propyl ester.
rac 3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid 2-hydroxy-2-methyl-propyl ester.
169. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfonylamino-phenyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfonylamino-phenyl)-amide.
170. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1H-tetrazol-5-ylmethyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1H-tetrazol-5-ylmethyl)-amide.
171. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-ureado-propyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-ureado-propyl)-amide.
172. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methylsulfanyl-phenyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methylsulfanyl-phenyl)-amide.
173. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfonyl-phenyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfonyl-phenyl)-amide.
174. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfinyl-phenyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfinyl-phenyl)-amide.
175. The compound:
3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]amino}-benzoic acid.
3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]amino}-benzoic acid.
176. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-carbamoyl-phenyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-carbamoyl-phenyl)-amide.
177. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide.
178. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide.
179. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-amino-phenyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-amino-phenyl)-amide.
180. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-acetylamino-phenyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-acetylamino-phenyl)-amide.
181. The compound:
rac 2-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-thiazole-4-carboxylic acid ethyl ester.
rac 2-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-thiazole-4-carboxylic acid ethyl ester.
182. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-amide.
183. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-oxo-1,6-dihydro-pyridin-3-yl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-oxo-1,6-dihydro-pyridin-3-yl)-amide.
184. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-oxo-1,6-dihydro-pyridin-3-yl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-oxo-1,6-dihydro-pyridin-3-yl)-amide.
185. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methylsulfanyl-phenyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methylsulfanyl-phenyl)-amide.
186. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonyl-phenyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonyl-phenyl)-amide.
187. The compound:
4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid tert-butyl ester.
4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid tert-butyl ester.
188. The compound:
4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.
4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.
189. The compound:
4-{[(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.
4-{[(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.
190. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-phenyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-phenyl)-amide.
191. The compound:
(2S,3R,4S,SR)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-phenyl)-amide.
(2S,3R,4S,SR)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-phenyl)-amide.
192. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonylamino-phenyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonylamino-phenyl)-amide.
193. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-trifluoro-methanesulfonylamino-phenyl)-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-trifluoro-methanesulfonylamino-phenyl)-amide.
194. The compound:
rac (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-amide.
rac (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-amide.
195. The compound:
rac (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(2-methyl-1H-tetrazol-5-yl)-phenyl]-amide.
rac (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(2-methyl-1H-tetrazol-5-yl)-phenyl]-amide.
196. The compound:
(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-oxo-1,6-dihydro-pyridin-3-yl)-amide.
(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-oxo-1,6-dihydro-pyridin-3-yl)-amide.
197. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide.
198. The compound:
(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide.
(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide.
199. The compound:
rac (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-methyl-1H-tetrazol-5-yl)-phenyl]-amide.
rac (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-methyl-1H-tetrazol-5-yl)-phenyl]-amide.
200. The compound:
rac (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxyl ic acid [4-(1-methyl-1H-tetrazol-5-yl)-phenyl]-amide.
rac (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxyl ic acid [4-(1-methyl-1H-tetrazol-5-yl)-phenyl]-amide.
201. The compound:
rac 5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester.
rac 5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester.
202. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide.
203. The compound:
(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide.
(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide.
204. The compound:
(2R,3S,4R,5 S)-3 -(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5 -(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-chloro-phenyl)-amide.
(2R,3S,4R,5 S)-3 -(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5 -(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-chloro-phenyl)-amide.
205. The compound:
rac (2R,3 S,4R,5 S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5 -(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-chloro-4-(1H-tetrazol-5-yl)-phenyl]-amide.
rac (2R,3 S,4R,5 S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5 -(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-chloro-4-(1H-tetrazol-5-yl)-phenyl]-amide.
206. The compound:
rac (2R,3 S,4R,5 S)-3 -(3 -ch loro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-fluoro-phenyl)-amide.
rac (2R,3 S,4R,5 S)-3 -(3 -ch loro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-fluoro-phenyl)-amide.
207. The compound:
rac (2R,3 S,4R,5 S)-3 -(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-fluoro-phenyl)-amide.
rac (2R,3 S,4R,5 S)-3 -(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-fluoro-phenyl)-amide.
208. The compound:
rac (2R,3 S,4R,5 S)-3 -(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-chloro-phenyl)-amide.
rac (2R,3 S,4R,5 S)-3 -(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-chloro-phenyl)-amide.
209. The compound:
rac (2R,3 S,4R,5 S)-3-(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5 -(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-chloro-phenyl)-amide.
rac (2R,3 S,4R,5 S)-3-(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5 -(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-chloro-phenyl)-amide.
210. The compound:
rac 4- { [(2R,3 S,4R,5 S)-3-(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-fluoro-benzoic acid tert-butyl ester.
rac 4- { [(2R,3 S,4R,5 S)-3-(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-fluoro-benzoic acid tert-butyl ester.
211. The compound:
rac (2 R,3 S,4R,5 S)-3 -(3 -ch loro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-ethylcarbamoyl-3-fluoro-phenyl)-amide.
rac (2 R,3 S,4R,5 S)-3 -(3 -ch loro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-ethylcarbamoyl-3-fluoro-phenyl)-amide.
212. The compound:
rac 4- { [(2R,3 S,4R,5 S)-3 -(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-fluoro-benzoic acid.
rac 4- { [(2R,3 S,4R,5 S)-3 -(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-fluoro-benzoic acid.
213. The compound:
rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-methoxy-pyridin-3-yl)-amide.
rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-methoxy-pyridin-3-yl)-amide.
214. The compound:
rac 3-({[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-benzoic acid methyl ester.
rac 3-({[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-benzoic acid methyl ester.
215. The compound:
rac 4-({[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]amino}-methyl)-benzoic acid methyl ester.
rac 4-({[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]amino}-methyl)-benzoic acid methyl ester.
216. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-chloro-phenyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-chloro-phenyl)-amide.
217. The compound:
(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-chloro-phenyl)-amide.
(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-chloro-phenyl)-amide.
218. The compound:
rac 4- { [(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-methoxy-benzoic acid methyl ester.
rac 4- { [(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-methoxy-benzoic acid methyl ester.
219. The compound:
rac 3-({[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]amino}-methyl)-benzoic acid.
rac 3-({[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]amino}-methyl)-benzoic acid.
220. The compound:
rac 4-({[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-benzoic acid.
rac 4-({[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-benzoic acid.
221. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-acetylamino-phenyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-acetylamino-phenyl)-amide.
222. The compound:
(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-acetylamino-phenyl)-amide.
(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-acetylamino-phenyl)-amide.
223. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonyl-phenyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonyl-phenyl)-amide.
224. The compound:
(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonyl-phenyl)-amide.
(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonyl-phenyl)-amide.
225. The compound:
rac 4- { [(R2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-methoxy-benzoic acid.
rac 4- { [(R2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-methoxy-benzoic acid.
226. The compound:
rac 5-bromo-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-methoxy-benzoic acid methyl ester.
rac 5-bromo-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-methoxy-benzoic acid methyl ester.
227. The compound:
rac 4- { [(R2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-methyl-benzoic acid methyl ester.
rac 4- { [(R2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-methyl-benzoic acid methyl ester.
228. The compound:
rac 2-Chloro-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester.
rac 2-Chloro-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester.
229. The compound:
rac 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-trifluoromethyl-benzoic acid methyl ester.
rac 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-trifluoromethyl-benzoic acid methyl ester.
230. The compound:
rac 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-methyl-benzoic acid.
rac 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-methyl-benzoic acid.
231. The compound:
rac 2-Chloro-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid.
rac 2-Chloro-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid.
232. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2H-[1,2,4]triazol-3-yl)-phenyl]-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2H-[1,2,4]triazol-3-yl)-phenyl]-amide.
233. The compound:
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(5-oxo-2,5-dihydro-1H-[1,2,4]triazol-3-yl)-phenyl]-amide.
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(5-oxo-2,5-dihydro-1H-[1,2,4]triazol-3-yl)-phenyl]-amide.
234. The compound:
rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
235. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
236. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
237. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
238. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
239. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
240. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
241. The compound:
rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbonyl-2-methyl-propyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbonyl-2-methyl-propyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
242. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
243. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
244. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
245. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-diethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-diethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
246. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-methyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-methyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
247. The compound:
rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
248. The compound:
rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
249. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
250. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
251. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-hydroxymethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-hydroxymethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
252. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
253. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
254. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1 -hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1 -hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
255. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
256. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
257. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
258. The compound:
rac-(2R,3 S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3 S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
259. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
260. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
261. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyI)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyI)-amide.
262. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[4-(2-hydroxy-ethoxy)-2,2-dimethyl-butyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[4-(2-hydroxy-ethoxy)-2,2-dimethyl-butyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
263. The compound:
rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
264. The compound:
rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
265. The compound:
rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
266. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-methanesulfonylamino-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-methanesulfonylamino-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
267. The compound:
rac-(2R,3S,4R,5S)-5-(4-benzoylamino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-5-(4-benzoylamino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
268. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-yl)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-yl)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
269. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
270. The compound:
rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
271. The compound:
rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-piperidin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-piperidin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
272. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
273. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-methyl-2-(tetrahydro-pyran-4-yl)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-methyl-2-(tetrahydro-pyran-4-yl)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
274. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide.
275. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide.
276. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide.
277. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide.
278. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide.
279. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide.
280. The compound:
rac-(2S,3R,4S,5R)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-5-(3-hydroxy-azetidine-1-carbonyl)-pyrrolidine-3-carbonitrile.
rac-(2S,3R,4S,5R)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-5-(3-hydroxy-azetidine-1-carbonyl)-pyrrolidine-3-carbonitrile.
281. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide.
282. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide.
283. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide.
284. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide.
285. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid amide.
286. The compound:
rac-6-{[R2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid methyl ester.
rac-6-{[R2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid methyl ester.
287. The compound:
rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide.
rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide.
288. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-acetylamino-pyridin-3-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-acetylamino-pyridin-3-yl)-amide.
289. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide.
290. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide.
291. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-amide.
292. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide.
293. The compound:
rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid methyl ester.
rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid methyl ester.
294. The compound:
rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid.
rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid.
295. The compound:
rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid amide.
rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid amide.
296. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid(6-chloro-pyridazin-3-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid(6-chloro-pyridazin-3-yl)-amide.
297. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-methyl-pyridin-3-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-methyl-pyridin-3-yl)-amide.
298. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]-amide.
299. The compound:
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]-amide.
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]-amide.
300. The compound:
rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-thiophene-2-carboxylic acid methyl ester.
rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-thiophene-2-carboxylic acid methyl ester.
301. The compound:
rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2 -dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-thiophene-2-carboxylic acid.
rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2 -dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-thiophene-2-carboxylic acid.
302. The compound:
5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl}-amino}-thiophene-2-carboxylic acid.
5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl}-amino}-thiophene-2-carboxylic acid.
303. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-methoxy-pyridin-4-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-methoxy-pyridin-4-yl)-amide.
304. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-hydroxy-pyridin-4-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-hydroxy-pyridin-4-yl)-amide.
305. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-acetyl-phenyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-acetyl-phenyl)-amide.
306. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-bromo-acetyl)-phenyl]-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-bromo-acetyl)-phenyl]-amide.
307. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-dimethylamino-acetyl)-phenyl]-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-dimethylamino-acetyl)-phenyl]-amide.
308. The compound:
rac-(5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-4H-[1,2,4]triazol-3-yl)-acetic acid.
rac-(5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-4H-[1,2,4]triazol-3-yl)-acetic acid.
309. The compound:
rac-(3- { [(2R,3S,4R,5S)-3-(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5 -(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino } -pyrazol-1 -yl)-acetic acid.
rac-(3- { [(2R,3S,4R,5S)-3-(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5 -(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino } -pyrazol-1 -yl)-acetic acid.
310. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1H-imidazol-4-ylmethyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1H-imidazol-4-ylmethyl)-amide.
311. The compound:
rac-(2S,3R,4S,5R)-4-(3 -chloro-2-fluoro-phenyl)-3 -(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl -propyl)-5-(2-oxa-6-aza-spiro [3 .3]heptane-6-carbonyl)-pyrrolidine-3-carbonitrile.
rac-(2S,3R,4S,5R)-4-(3 -chloro-2-fluoro-phenyl)-3 -(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl -propyl)-5-(2-oxa-6-aza-spiro [3 .3]heptane-6-carbonyl)-pyrrolidine-3-carbonitrile.
312. The compound:
rac-1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-azetidine3-carboxylic acid.
rac-1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-azetidine3-carboxylic acid.
313. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide.
314. The compound:
rac-(2R,3S,4R,5S)-3-(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-carbamoylmethyl-1H-pyrazol-3-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-carbamoylmethyl-1H-pyrazol-3-yl)-amide.
315. The compound:
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide.
rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide.
316. The compound:
rac-(2R,3R,4R,5S)-3 -(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl -propyl)-pyrrolidine-2 -carboxylic acid (3 -methanesulfonylamino-propyl)-amide.
rac-(2R,3R,4R,5S)-3 -(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl -propyl)-pyrrolidine-2 -carboxylic acid (3 -methanesulfonylamino-propyl)-amide.
317. The compound:
chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3- yl} -amide.
chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3- yl} -amide.
318. The compound:
chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3- yl } -amide.
chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3- yl } -amide.
319. The compound:
rac-1- [(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-cyclopropane carboxylic acid.
rac-1- [(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-cyclopropane carboxylic acid.
320. The compound:
rac-(2R,35,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(4-hydroxy-piperidin-4-ylmethyl)-1H-pyrazol-3-yl]-amide.
rac-(2R,35,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(4-hydroxy-piperidin-4-ylmethyl)-1H-pyrazol-3-yl]-amide.
321. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-acetyl-thiophen-3-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-acetyl-thiophen-3-yl)-amide.
322. The compound:
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-carbamoyl-thiophen-3-yl)-amide.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-carbamoyl-thiophen-3-yl)-amide.
323. The compound:
rac- (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-((S)-3-dimethylamino-2-hydroxy-propyl)-1H-pyrazol-3-yl}-amide.
rac- (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-((S)-3-dimethylamino-2-hydroxy-propyl)-1H-pyrazol-3-yl}-amide.
324. The compound:
rac-4-1[(2R,3S,4R,5S)-3 -(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carbonyl] -amino } -benzoic acid.
rac-4-1[(2R,3S,4R,5S)-3 -(3 -chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carbonyl] -amino } -benzoic acid.
325. The compound:
rac-[4-(3-{ [(2R,35,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-ylmethyl)-4-hydroxy-piperidin-1-yl]-acetic acid.
rac-[4-(3-{ [(2R,35,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-ylmethyl)-4-hydroxy-piperidin-1-yl]-acetic acid.
326. The compound:
rac-4- [(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester.
rac-4- [(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester.
327. The compound:
rac-4-{[(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]amino}-benzoic acid.
rac-4-{[(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]amino}-benzoic acid.
328. The compound:
rac-4- [(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]amino}-benzoic acid methyl ester.
rac-4- [(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]amino}-benzoic acid methyl ester.
329. The compound:
rac-4-{[(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.
rac-4-{[(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.
330. The compound:
rac-4- [(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester.
rac-4- [(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester.
331. The compound:
rac-4- [(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.
rac-4- [(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.
332. The compound:
rac-4- [(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester.
rac-4- [(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester.
333. The compound:
rac-4-{ [(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.
rac-4-{ [(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid.
334. The compound:
rac-4- [(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester.
rac-4- [(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester.
335. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 334 together with pharmaceutically acceptable excipients or carriers.
336. A compound according to any one of claims 1 to 334 for use as a medicament.
337. A compound according to any one of claims 1 to 334 for use as a medicament for the treatment of cancer.
338. The compound according to claim 337, wherein said medicament is for the treatment of solid tumors.
339. The compound according to claim 338, wherein said solid tumor is a breast, colon, lung or prostate tumor.
340. Use of a compound according to any one of claims 1 to 334 for the manufacture of medicaments for the treatment of cancer.
34L Use of a compound according to any one of claims 1 to 334 for the treatment of cancer.
342. The use of claim 340 or 341, wherein said cancer is a solid tumor.
343. The use of claim 342, wherein said solid tumor is a breast, colon, lung or prostate tumor.
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| US61/097,884 | 2008-09-18 | ||
| US22563309P | 2009-07-15 | 2009-07-15 | |
| US61/225,633 | 2009-07-15 | ||
| PCT/EP2009/061610 WO2010031713A1 (en) | 2008-09-18 | 2009-09-08 | Substituted pyrrolidine-2-carboxamides |
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| US8354444B2 (en) * | 2008-09-18 | 2013-01-15 | Hoffmann-La Roche Inc. | Substituted pyrrolidine-2-carboxamides |
| US8017607B2 (en) | 2009-10-14 | 2011-09-13 | Hoffmann-La Roche Inc. | N-substituted-pyrrolidines as inhibitors of MDM2-P-53 interactions |
| US20110118283A1 (en) * | 2009-11-17 | 2011-05-19 | Qingjie Ding | Substituted Pyrrolidine-2-Carboxamides |
| US8088815B2 (en) * | 2009-12-02 | 2012-01-03 | Hoffman-La Roche Inc. | Spiroindolinone pyrrolidines |
| JO2998B1 (en) | 2010-06-04 | 2016-09-05 | Amgen Inc | Piperidinone derivatives as mdm2 inhibitors for the treatment of cancer |
| US20120010235A1 (en) * | 2010-07-12 | 2012-01-12 | Xin-Jie Chu | N-substituted pyrrolidines |
| US20120046306A1 (en) * | 2010-08-18 | 2012-02-23 | David Joseph Bartkovitz | Substituted Heteroaryl Spiropyrrolidine MDM2 Antagonists |
| CN101898998B (en) * | 2010-08-25 | 2012-09-19 | 武汉武药科技有限公司 | Method for preparing tirofiban hydrochloride intermediate |
| US20120065210A1 (en) | 2010-09-15 | 2012-03-15 | Xin-Jie Chu | Substituted hexahydropyrrolo[1,2-c]imidazolones |
| WO2012076513A1 (en) * | 2010-12-09 | 2012-06-14 | F. Hoffmann-La Roche Ag | 3-cyano-1-hydroxymethyl-2-phenylpyrrolidine derivatives as inhibitors of mdm2-p53 interactions useful for the treatment of cancer |
| BR112013023175B1 (en) | 2011-03-10 | 2022-11-16 | Daiichi Sankyo Company, Limited | COMPOUND, PHARMACEUTICAL COMPOSITION, AND COMPOUND USE |
| MX352672B (en) | 2011-09-27 | 2017-12-04 | Amgen Inc | Heterocyclic compounds as mdm2 inhibitors for the treatment of cancer. |
| US8993614B2 (en) | 2012-03-15 | 2015-03-31 | F. Hoffmann-La Roche Ag | Substituted pyrrolidine-2-carboxamides |
| MX2014014229A (en) * | 2012-05-30 | 2015-02-17 | Hoffmann La Roche | Substituted pyrrolidine-2-carboxamides. |
| TWI586668B (en) | 2012-09-06 | 2017-06-11 | 第一三共股份有限公司 | Crystals of dispiropyrrolidine derivative |
| US11407721B2 (en) | 2013-02-19 | 2022-08-09 | Amgen Inc. | CIS-morpholinone and other compounds as MDM2 inhibitors for the treatment of cancer |
| WO2014134201A1 (en) | 2013-02-28 | 2014-09-04 | Amgen Inc. | A benzoic acid derivative mdm2 inhibitor for the treatment of cancer |
| CA2906538C (en) | 2013-03-14 | 2021-02-02 | Ana Gonzalez Buenrostro | Heteroaryl acid morpholinone compounds as mdm2 inhibitors for the treatment of cancer |
| JOP20200296A1 (en) | 2013-06-10 | 2017-06-16 | Amgen Inc | Processes of Making and Crystalline Forms of a MDM2 Inhibitor |
| EP3017061B1 (en) | 2013-07-03 | 2019-01-02 | F. Hoffmann-La Roche AG | Mrna-based gene expression for personalizing patient cancer therapy with an mdm2 antagonist |
| CN106794171B (en) | 2014-04-17 | 2020-03-24 | 密歇根大学董事会 | MDM2 inhibitors and methods of treatment using the same |
| CN107427501B (en) | 2015-02-20 | 2023-12-01 | 第一三共株式会社 | Methods of treating cancer by combination use |
| KR20170134462A (en) | 2015-04-13 | 2017-12-06 | 다이이찌 산쿄 가부시키가이샤 | Treatment method combining mdm2 inhibitor and btk inhibitor |
| GB201517217D0 (en) | 2015-09-29 | 2015-11-11 | Astex Therapeutics Ltd And Cancer Res Technology Ltd | Pharmaceutical compounds |
| GB201517216D0 (en) | 2015-09-29 | 2015-11-11 | Cancer Res Technology Ltd And Astex Therapeutics Ltd | Pharmaceutical compounds |
| CA3040840A1 (en) | 2016-10-17 | 2018-04-26 | Daiichi Sankyo Company, Limited | Combined use of mdm2 inhibitor and dna methyltransferase inhibitor for cancer treatment |
| KR102122469B1 (en) | 2016-11-01 | 2020-06-12 | 주식회사 엘지화학 | Modified diene polymer and preparation method thereof |
| GB201704965D0 (en) | 2017-03-28 | 2017-05-10 | Astex Therapeutics Ltd | Pharmaceutical compounds |
| GB201704966D0 (en) | 2017-03-28 | 2017-05-10 | Astex Therapeutics Ltd | Pharmaceutical compounds |
| JOP20200001A1 (en) | 2017-07-11 | 2022-10-30 | Vertex Pharma | Carboxamides as modulators of sodium channels |
| WO2019213106A1 (en) | 2018-04-30 | 2019-11-07 | Teva Pharmaceuticals International Gmbh | Solid state forms of idasanutlin |
| US20210371406A1 (en) | 2018-10-03 | 2021-12-02 | Rijksuniversiteit Groningen | Photoresponsive Nutlin Derivatives and Uses Thereof |
| CR20220316A (en) | 2019-12-06 | 2022-10-07 | Vertex Pharma | Substituted tetrahydrofurans as modulators of sodium channels |
| US11827627B2 (en) | 2021-06-04 | 2023-11-28 | Vertex Pharmaceuticals Incorporated | N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels |
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| US7491394B2 (en) * | 2001-02-15 | 2009-02-17 | The Board Of Trustees Of The University Of Illinois | Cytotoxic factors for modulating cell death |
| TW200404796A (en) * | 2002-08-19 | 2004-04-01 | Ono Pharmaceutical Co | Nitrogen-containing compound |
| CA2598690C (en) * | 2005-02-22 | 2011-11-15 | The Regents Of The University Of Michigan | Small molecule inhibitors of mdm2 and uses thereof |
| JP2009542666A (en) * | 2006-06-30 | 2009-12-03 | シェーリング コーポレイション | Substituted piperidines that increase P53 activity and uses thereof |
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